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Objectives To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Methods Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median age of onset 69.3 years (interquartile range 62.1–77.6)]. Peptide nucleic acid–clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR or targeted amplicon deep sequencing was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and -negative patients and assessed the diagnostic value of our system using receiver operating characteristics (ROC) curve analysis. Results Forty patients (44.9%) with reported pathogenic UBA1 variants were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering age >50 years, cutaneous lesions, lung involvement, chondritis and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908). Conclusion Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants. [ABSTRACT FROM AUTHOR]

This article examines the long-term kidney function of individuals with Lowe syndrome, a genetic disorder characterized by ocular disease, central nervous system disorder, and kidney disease. The study analyzed a large group of pediatric and adult patients with Lowe syndrome and found that all patients had congenital cataracts, CNS involvement, and Fanconi syndrome. The study also investigated the estimated glomerular filtration rate (eGFR) and clinical prognostic factors in these patients. The results indicate that kidney disease is a significant prognostic factor in Lowe syndrome, and further research is necessary to understand the progression of chronic kidney disease in adult patients with this syndrome. Another study analyzed the progression of chronic kidney disease (CKD) in individuals with Lowe syndrome, a rare genetic disorder. The study discovered that CKD progressed rapidly after the age of 10, with 84% of patients developing severe CKD after the age of 20. Nephrocalcinosis and hypercalciuria did not have a significant impact on kidney function. The study also found that age was the only factor significantly associated with kidney function. These findings suggest that the majority of individuals with Lowe syndrome develop end-stage kidney disease by their fourth decade of life. [Extracted from the article]

The authors comment on a study by A. Maeda and colleagues which showed that the combination of regular polymerase chain reaction (PCR) and peptide nucleic acid-clamping (PNA-PCR) is effective in detecting somatic UBA1 variants with high sentistivity and specificity. Topics discussed include finding on the proportion of vacuolated early myeloid and erythroid precursor cells in bone marrow aspirations, UBA1 sequencing performed in 53 patients, and observation on the score proposed by Maeda et al.

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]

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]

Loss-of-function mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome in males. Christianson syndrome involves endosome dysfunction leading to early cerebellar degeneration, as well as later-onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in post-mortem studies. In addition, there is reported evidence of modulation of amyloid-β levels in experimental models wherein NHE6 expression was targeted. We have recently shown that loss of NHE6 causes defects in endosome maturation and trafficking underlying lysosome deficiency in primary mouse neurons in vitro. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously-expressed amyloid-β and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously-expressed (non-transgenic) tau or amyloid-β. Therefore, to study neurodegeneration in Christianson syndrome and the possibility of amyloid-β and tau pathology, we generated an NHE6-null rat model of Christianson syndrome using CRISPR-Cas9 genome-editing. Here, we present the sequence of pathogenic events in neurodegenerating NHE6-null male rat brains across the lifespan. NHE6-null rats demonstrated an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observed biochemical and in situ evidence of both amyloid-β and tau aggregation in the aged NHE6-null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observed tau deposition in both neurons and glia, as has been reported in Christianson syndrome post-mortem studies previously. In summary, this experimental model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously-expressed amyloid-β and tau. This NHE6-null rat will serve as a new robust model for Christianson syndrome. Furthermore, these studies provide evidence for linkages between endolysosome dysfunction and neurodegeneration involving protein aggregations, including amyloid-β and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer's disease and related dementias. [ABSTRACT FROM AUTHOR]

The rare genetic disorder X-linked hypophosphatemia (XLH) is often exclusively considered to impact children, and, as such, adult patients with XLH may receive inadequate care because their symptoms are not associated with XLH. However, studies have shown that XLH has long-term adverse health consequences that continue throughout adulthood requiring comprehensive lifelong care. Indeed, XLH impacts patients' whole body, whole life, and whole family. XLH does not just affect the bones; symptoms are chronic and progressive, worsening throughout adulthood, and the burden of XLH overflows into the lives of a patient's family, friends, peers, and colleagues. To ensure early recognition, comprehensive care, and adequate management of XLH, there are key steps that clinicians can incorporate into their daily practice. These include education, a multidisciplinary approach, open communication, and support. Clinician education on rare disorders such as XLH is critical, and healthcare professionals (HCPs) should ensure that patients and their caregivers have access to XLH-related information. As a whole-body disorder, XLH requires a coordinated approach to treatment across specialties. Frequent open communication among members of the healthcare team is needed to increase HCPs' knowledge about XLH, and open communication must extend to the patient as well to ensure the patient's concerns and needs are addressed and treatment is tailored to their specific individual needs. Multiple networks of support, including social and psychological support, should be offered to patients and their families. A basic understanding that XLH affects patients' whole bodies, whole lives, and whole families is the first step toward accomplishing improved patient care. [ABSTRACT FROM AUTHOR]

Objective To gain insight in the expression profile of long non-coding RNAs (lncRNAs) in OA subchondral bone. Methods RNA sequencing data of macroscopically preserved and lesioned OA subchondral bone of patients that underwent joint replacement surgery due to OA (N  = 22 pairs; 5 hips, 17 knees, Research osteoArthrits Articular Tissue (RAAK study) was run through an in-house pipeline to detect expression of lncRNAs. Differential expression analysis between preserved and lesioned bone was performed. Spearman correlations were calculated between differentially expressed lncRNAs and differentially expressed mRNAs identified previously in the same samples. Primary osteogenic cells were transfected with locked nucleic acid (LNA) GapmeRs targeting AC005165.1 lncRNA, to functionally investigate its potential mRNA targets. Results In total, 2816 lncRNAs were well-expressed in subchondral bone and we identified 233 lncRNAs exclusively expressed in knee and 307 lncRNAs exclusively in hip. Differential expression analysis, using all samples (N  = 22 pairs; 5 hips, 17 knees), resulted in 21 differentially expressed lncRNAs [false discovery rate (FDR) < 0.05, fold change (FC) range 1.19–7.39], including long intergenic non-protein coding RNA (LINC) 1411 (LINC01411, FC = 7.39, FDR = 2.20 × 10−8), AC005165.1 (FC = 0.44, FDR = 2.37 × 10−6) and empty spiracles homeobox 2 opposite strand RNA (EMX2OS, FC = 0.41, FDR = 7.64 × 10−3). Among the differentially expressed lncRNAs, five were also differentially expressed in articular cartilage, including AC005165.1 , showing similar direction of effect. Downregulation of AC005165.1 in primary osteogenic cells resulted in consistent downregulation of highly correlated frizzled related protein (FRZB). Conclusion The current study identified a novel lncRNA, AC005165.1 , being dysregulated in OA articular cartilage and subchondral bone. Downregulation of AC005165.1 caused a decreased expression of OA risk gene FRZB , an important member of the wnt pathway, suggesting that AC005165.1 could be an attractive potential therapeutic target with effects in articular cartilage and subchondral bone. [ABSTRACT FROM AUTHOR]

The article describes a case of a male patient with early-onset of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. Topics mentioned include the link of somatic mutations in blood cells with systemic inflammation, the treatment of the syndrome using topical non-sterioidcal anti-inflammatory drugs, and the clinical and genetic characteristics of the syndrome.

Background: Very few recent nationwide studies have assessed the epidemiology of cleft lip with or without palate (CL/P). The purpose of this study was to identify the prevalence, risk of premature births, mortality and cause of death of CL/P.Methods: This nationwide population-based cohort study evaluated all 5 747 830 live births in South Korea, including CL/P infants, from 2006 to 2018. The prevalence with trend analysis, risk of premature births, mortality and cause of death of CL/P with or without associated syndromes (non-syndromic, syndromic CL/P) and subgroups (cleft lip only, cleft palate only, cleft lip with palate) were evaluated.Results: Among 5 747 830 live births, 11 284 children were identified as having CL/P during the study period. The annual prevalence was 1.96 per 1000 births. The prevalence ratio, which shows the trend during the period, was 1.021. Both non-syndromic and syndromic CL/P children had higher risk of premature births compared with children without CL/P (odds ratio: non-syndromic 1.43, syndromic 5.29). The mortality rates per 1000 person-years were 0.39 for children without CL/P, 0.98 for non-syndromic CL/P children and 12.20 for syndromic CL/P children. The causes of deaths were not different for children without CL/P in non-syndromic CL/P, but the most common cause of deaths was cardiovascular anomalies in syndromic CL/P.Conclusion: The reported prevalence of 1.96 per 1000 births is one of the highest prevalences worldwide. CL/P children had high risks of premature births and risk of mortality. The most common cause of deaths was cardiovascular anomalies. [ABSTRACT FROM AUTHOR]

Dosage compensation involves chromosome-wide gene regulatory mechanisms which impact higher order chromatin structure and are crucial for organismal health. Using a genetic approach, we identified Argonaute genes which promote dosage compensation in Caenorhabditis elegans. Dosage compensation in C. elegans hermaphrodites is initiated by the silencing of xol-1 and subsequent activation of the dosage compensation complex which binds to both hermaphrodite X chromosomes and reduces transcriptional output by half. A hallmark phenotype of dosage compensation mutants is decondensation of the X chromosomes. We characterized this phenotype in Argonaute mutants using X chromosome paint probes and fluorescence microscopy. We found that while nuclear Argonaute mutants hrde-1 and nrde-3, as well as mutants for the piRNA Argonaute prg-1, exhibit derepression of xol-1 transcripts, they also affect X chromosome condensation in a xol-1-independent manner. We also characterized the physiological contribution of Argonaute genes to dosage compensation using genetic assays and found that hrde-1 and nrde-3 contribute to healthy dosage compensation both upstream and downstream of xol-1. [ABSTRACT FROM AUTHOR]

Study Objectives: To describe early diagnostic clues in Cyclin-Dependent Kinase-Like 5 (CDKL5) refractory encephalopathy, to improve treatment strategies. Methods: We retrospectively studied 35 patients (25 females, 10 males) with CDKL5 gene mutations or deletion, focusing on their early seizure semiology, the electroencephalogram (EEG) pattern, the effect of treatment, and developmental outcome. Results: The first seizures were recognizable and consisted of tonic, then clonic, and spasms phases, occurring in sleep at a median age of 6 weeks. Clusters of spasms were observed in quiet sleep or slow-wave sleep (SWS), with screaming, staring, and arms' extension that mimicked sleep terror in 28 of 35 patients (80%). Programmed awakening prevented these spasms in 9 of 16 patients and small doses of clonazepam given at night improved epilepsy in 14 of 23 patients. Conclusions: Peculiar seizures with spasms starting in SWS are an early diagnostic clue in infants with CDKL5 encephalopathy. Sleep video-EEG polygraphy is an easy tool to disclose these early seizures and epileptic spasms in infants during the first months of life while polysomnography is unlikely to give a contribution at that early age. While conventional antiepileptic treatment and corticosteroids are poorly, transiently, or not efficient, therapeutic strategy used for sleep terror could help, although the mechanism of spasms generation in SWS needs to be elucidated. [ABSTRACT FROM AUTHOR]

The article describes the case of a 69-year-old man with acute-onset polyarthralgia and fever in March 2015. Topics discussed include finding on a previous skin biopsy of his lower limbs in April 2014, possibility of rheumatoid vasculitis in the patient, and findings that led to the diagnosis of VEXAS syndrome.

Objective Tetralogy of Fallot (TOF) is one of the most common congenital abnormalities that need early intervention. Here, for the first time, we report a nonsyndromic form of TOF caused by a novel variant in the FLNA gene in 2 siblings of an Iranian family. Methods The family underwent a complete workup, including karyotyping, sequencing of 6 common genes in congenital heart diseases (GATA4, NKX2-5, ZIC3, FOXH1, NODAL, and GJA1), array comparative genomic hybridization, multiplex ligation-dependent probe amplification, and whole-exome sequencing. Segregation and in silico analysis were also conducted for the identified variant. Results A variant, c.3415C>T, in the FLNA gene was found in both affected brothers in this family; this variant was heterozygous in their mother. Bioinformatics tools predicted the variant as a pathogenic one. Conclusion Many allelic disorders have been reported for FLNA mutations. Mutations in this gene may cause a nonsyndromic congenital form of TOF. [ABSTRACT FROM AUTHOR]

Objectives X-Linked hypophosphataemic rickets (XLH) is a rare multi-systemic disease of mineral homeostasis that has a prominent skeletal phenotype. The aim of this study was to describe additional comorbidities in XLH patients compared with general population controls. Methods The Clinical Practice Research Datalink (CPRD) GOLD was used to identify a cohort of XLH patients (1995–2016), along with a non-XLH cohort matched (1 : 4) on age, sex and GP practice. Using the CALIBER portal, phenotyping algorithms were used to identify the first diagnosis (and associated age) of 273 comorbid conditions during patient follow-up. Fifteen major disease categories were used and the proportion of patients having ≥1 diagnosis was compared between cohorts for each category and condition. Main analyses were repeated according to the Index of Multiple Deprivation (IMD). Results There were 64 and 256 patients in the XLH and non-XLH cohorts, respectively. There was increased prevalence of endocrine [OR 3.46 (95% CI: 1.44, 8.31)] and neurological [OR 3.01 (95% CI: 1.41, 6.44)] disorders among XLH patients. Across all specific comorbidities, four were at least twice as likely to be present in XLH cases, but only depression met the Bonferroni threshold: OR 2.95 (95% CI: 1.47, 5.92). Distribution of IMD among XLH cases indicated greater deprivation than the general population. Conclusion We describe a higher risk of mental illness in XLH patients compared with matched controls, and greater than expected deprivation. These findings may have implications for clinical practice guidelines and decisions around health and social care provision for these patients. [ABSTRACT FROM AUTHOR]

Study Question: What is the clinical validity and utility of preconception Expanded Carrier Screening (ECS) application on the management of prospective parents?Summary Answer: The high detection rate of at-risk couples (ARCs) and the high proportion opting for IVF/preimplantation genetic testing (PGT) treatment demonstrate the clinical utility of ECS in the preconception space in IVF and general population.What Is Known Already: About 2-4% of couples are at risk of conceiving a child with an autosomal recessive or X-linked genetic disorder. In recent years, the increasing cost-effectiveness of genetic diagnostic techniques has allowed the creation of ECS panels for the simultaneous detection of multiple recessive disorders. Comprehensive preconception genetic screening holds the potential to significantly improve couple's genetic risk assessment and reproductive planning to avoid detectable inheritable genetic offspring.Study Design, Size, Duration: A total of 3877 individuals without a family history of genetic conditions were analyzed between January 2017 and January 2020. Of the enrolled individuals, 1212 were gamete donors and 2665 were patients planning on conceiving from both the IVF and the natural conception group. From the non-donor cohort, 1133 were analyzed as individual patients, while the remaining ones were analyzed as couples, for a total of 766 couples.Participants/materials, Setting, Methods: A focused ECS panel was developed following American College of Obstetrics and Gynecology ACOG-recommended criteria (prevalence, carrier rate, severity), including highly penetrant severe childhood conditions. Couples were defined at-risk when both partners carried an autosomal recessive pathogenic/likely pathogenic variant (PLP) on the same gene or when the woman was a carrier of an X-linked PLP variant. ARC detection rate defined the clinical validity of the ECS approach. Clinical utility was evaluated by monitoring ARCs reproductive decision making.Main Results and the Role Of Chance: A total of 402 individuals (10.4%) showed PLP for at least one of the genes tested. Among the 766 couples tested, 173 showed one carrier partner (22.6%), whereas 20 couples (2.6%) were found to be at increased risk. Interestingly, one ARC was identified as a result of cascade testing in the extended family of an individual carrying a pathogenic variant on the Survival Of Motor Neuron 1SMN1 gene. Of the identified ARCs, 5 (0.7%) were at risk for cystic fibrosis, 5 (0.7%) for fragile X syndrome, 4 (0.5%) for spinal muscular atrophy, 4 (0.5%) for Beta-Thalassemia/Sickle Cell Anemia, 1 (0.1%) for Smith-Lemli-Opitz Syndrome and 1 (0.1%) for Duchenne/Becker Dystrophy. Fifteen ARCs were successfully followed up from both the IVF and the natural conception groups. All of these (15/15) modified their reproductive planning by undergoing ART with Preimplantation Genetic Testing for Monogenic disease and Aneuploidies (PGT-M and PGT-A). To date, 6/15 (40%) couples completed their PGT cycle with euploid/unaffected embryos achieving a pregnancy after embryo transfer and three of them have already had an unaffected baby.Limitations, Reasons For Caution: The use of a limited panel of core gene-disease pairs represents a limitation on the research perspective as it can underestimate the rate of detectable carriers and ARCs in this cohort of prospective parents. Expanding the scope of ECS to a larger panel of conditions is becoming increasingly feasible, thanks to a persistent technological evolution and progressive cataloging of gene-disease associations.Wider Implications Of the Findings: These results highlight the potential clinical validity and utility of ECS in reducing the risk of a pregnancy affected by a detectable inheritable genetic condition. The steady reduction in the costs of genetic analyses enables the expansion of monogenic testing/screening applications at the preimplantation stage, thus, providing valid decisional support and reproductive autonomy to patients, particularly in the context of IVF.Study Funding/competing Interest(s): No external funding was used for this study. A.C., M.F., S.C., M.P., L.G., and C.P. are employees of Igenomix Italy. C.S. is the head of the scientific board of Igenomix.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background Fabry disease is a rare, X-linked genetic disorder that, if untreated in patients with the Classic phenotype, often progresses to end-stage kidney disease. This meta-analysis determined the effect of agalsidase beta on loss of estimated glomerular filtration rate (eGFR) in the Classic phenotype using an expansive evidence base of individual patient-level data. Methods The evidence base included four Sanofi-Genzyme studies and six studies from a systematic literature review. These were restricted to Classic Fabry patients meeting the eligibility criteria from Phases III and IV agalsidase beta trials, including 315 patients (161 treated). Linear regression was first used to model annual change in eGFR for each patient and the resulting annualized eGFR slopes were modelled with treatment and covariates using quantile regression. These results were then used to estimate median annualized eGFR change in agalsidase beta treated versus untreated groups. Results Imbalances across treatment groups were found in baseline age, sex and proteinuria, but not in the use of renin–angiotensin system blockers. The adjusted model suggests that treated (agalsidase beta) patients experienced a slower median eGFR decrease [2.46 mL/min/1.73 m2/year slower; 95% confidence interval (CI) 0.63–4.29; P = 0.0087] than comparable untreated patients. The median eGFR decrease was 2.64 mL/min/1.73 m2/year slower (95% CI 0.53–4.78; P = 0.0141) in treated Classic males. Conclusions Using an expansive evidence base and robust modelling approach, these data indicate that agalsidase beta-treated patients with the Classic phenotype conserve their renal function better than untreated patients. [ABSTRACT FROM AUTHOR]

Background Anderson–Fabry disease (AFD) is an X-linked lysosomal storage disorder resulting from a mutation of alpha-galactosidase A gene (GLA), causing deficiency in alpha-galactosidase activity. The enzyme deficit can lead to storage of globotriaosylceramide in various organs including heart. Studies suggest that vasospastic angina (VSA) is associated with AFD. Case summary This clinical case series aimed to present two female patients with AFD, including progressive cardiac involvement: a 50-year-old woman (patient number 1) and a 39-year-old woman (patient number 2) who are siblings with a male AFD patient harbouring p. Arg342Glu missense variant in alpha-galactosidase A gene (GLA), who suffered VSA and subsequent ventricular fibrillation. Enzymatic tests and genetic analysis confirmed AFD in both female patients and histological tests revealed globotriaosylceramide deposits in their hearts. In patient number 1, a 12-lead electrocardiography and transthoracic echocardiography revealed cardiac hypertrophy. Coronary angiography revealed no organic coronary artery stenosis and vasospasms was induced by spasm provocation test. In patient number 2, no signs of cardiac hypertrophy were found, and coronary arteries had no organic stenosis with negative spasm provocation test. Both patients received enalapril therapy and enzyme replacement therapy (ERT). Discussion Different phenotype of AFD was occurred even with the same genetic variant in female heterozygote patients. The duration of exposing accumulation of Gb3 might affect cardiac hypertrophy and vasospasms. Coronary angiography with acetylcholine provocation test should be considered in female AFD patient, especially in case with cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Context: We characterized linear growth in infants and children with X-linked hypophosphatemia (XLH).Objective: Provide linear growth curves for children with XLH from birth to early adolescence.Design: Data from 4 prior studies of XLH were pooled to construct growth curves. UX023-CL002 was an observational, retrospective chart review. Pretreatment data were collected from 3 interventional trials: two phase 2 trials (UX023-CL201, UX023-CL205) and a phase 3 trial (UX023-CL301).Setting: Medical centers with expertise in treating XLH.Patients: Children with XLH, 1-14 years of age.Intervention: None.Main Outcome Measure: Height-for-age linear growth curves, including values for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles for children with XLH compared to population norms.Results: A total of 228 patients (132 girls, 96 boys) with 2381 height measurements were included. Nearly all subjects (> 99%) reported prior management with supplementation therapy. Compared to the Center for Disease Control and Prevention growth curves, boys at age 3 months, 6 months, 9 months, 1 year, and 2 years had median height percentiles of 46%, 37%, 26%, 18%, and 5%, respectively; for girls the median height percentiles were 52%, 37%, 25%, 18%, and 7%, respectively. Annual growth in children with XLH fell below that of healthy children near 1 year of age and progressively declined during early childhood, with all median height percentiles < 8% between 2 and 12 years old.Conclusion: Children with XLH show decreased height gain by 1 year of age and remain below population norms thereafter. These data will help evaluate therapeutic interventions on linear growth for pediatric XLH. [ABSTRACT FROM AUTHOR]

Primary B-cell immunodeficiencies are risk factors for the generation of vaccine-derived polioviruses. We report immunodeficiency-associated vaccine-derived poliovirus serotype 3 in an 11-week-old boy with X-linked agammaglobulinemia. Unique characteristics of this case include early age of presentation, high viral evolutionary rate, and the child's perinatal exposure to human immunodeficiency virus. [ABSTRACT FROM AUTHOR]

In the article, the authors present a case of a 9-year-old boy born to consanguineous parents who was rushed due to neurological delay and irritability from the early months of his life to discuss Aicardi-Goutières Syndrome (AGS) linked to novel RNASEH2C gene variant combined with X-linked agammaglobulinemia (XLA) due to BTK deficiency. Also cited is the use of next generation sequencing, particularly whole exome sequencing (WES), in testing multiple genes.

X-linked dystonia-parkinsonism is a neurodegenerative movement disorder characterized by adult-onset dystonia combined with parkinsonism over the disease course. Previous imaging and pathological findings indicate exclusive striatal atrophy with predominant pathology of the striosomal compartment in the dystonic phase of X-linked dystonia-parkinsonism. The striosome occupies 10-15% of the entire striatal volume and the density of striosomes follows a rostrocaudal gradient with the rostral striatum being considered striosome-rich. Recent quantitative MRI analyses provided evidence for an additional involvement of the white matter and the pallidum. In this study, we aimed to (i) disentangle the degree of atrophy in the different subdivisions of the striatum; (ii) investigate changes of cortical morphology; and (iii) elucidate the role of the cerebellum in X-linked dystonia-parkinsonism. T1-weighted MRI scans were acquired in 17 male X-linked dystonia-parkinsonism patients with predominant dystonia (40.1 ± 7.5 years) and 17 ethnicity-matched male healthy controls (35.2 ± 7.4 years). Voxel-based morphometry used a region of interest-based approach for the basal ganglia and primary motor cortex, whole brain analysis, and a separate analysis of the cerebellum. Cortical thickness and subcortical volume were measured. Volume loss in X-linked dystonia-parkinsonism affected all parts of the striatum (-29% voxel intensity) but was most pronounced in the associative subdivision (-41%; P < 0.001). The volume loss also involved the external and internal pallidum, albeit to a lesser extent than the striatum (-19% and -12%, P<0.001). Cortical thickness was reduced in the frontal (-4.3%) and temporal cortex (-6.1%). In addition, we found grey matter pathology in the associative part of the cerebellum and increased voxel intensities in the anterior sensorimotor part of the cerebellum and the dorsal ponto-mesencephalic brainstem. Taken together, our analysis of subcortical and cortical grey matter in the dystonic phase of X-linked dystonia-parkinsonism showed that (i) the striosome-enriched rostral striatum was most severely affected; and (ii) cortical thickness was only reduced in those regions that predominantly have anatomical connections to striosomes. Moreover, the cerebellum may be implicated in both disease-related and compensatory changes, highlighting the significance of the cerebellum in the pathophysiology of dystonia. [ABSTRACT FROM AUTHOR]

Objectives. Phosphoribosylpyrophosphate synthetase (PRPS1) superactivity is an X-linked disorder char-acterized by urate overproduction Online Mendelian Inheritance in Man (OMIM) gene reference 300661. This condition is thought to rarely affect women, and when it does, the clinical presentation is mild. We describe a 16-year-old African American female who developed progressive tophi, nephrolithiasis and acute kidney failure due to urate overproduction. Family history included a mother with tophaceous gout who developed end-stage kidney disease due to nephrolithiasis and an affected sister with polyarticular gout. The main aim of this study was to describe the clinical manifestations of PRPS1 superactivity in women. Methods. Whole exome sequencing was performed in affected females and their fathers. Results. Mutational analysis revealed a new c.520G > A (p.G174R) mutation in the PRPS1 gene. The mutation resulted in decreased PRPS1 inhibition by ADP. Conclusion. Clinical findings in previously reported females with PRPS1 superactivity showed a high clinical penetrance of this disorder with a mean serum urate level of 8.5(4.1) mg/dl [506 (247) µmol/l] and a high prevalence of gout. These findings indicate that all women in families with PRPS1 superactivity should be genetically screened for a mutation (for clinical management and genetic counselling). In addition, women with tophaceous gout, gout presenting in childhood, or a strong family history of severe gout should be considered for PRPS1 mutational analysis. [ABSTRACT FROM AUTHOR]

Background X-linked agammaglobulinemia (XLA) is a primary immunodeficiency associated with mutations in the B cell tyrosine kinase gene leading to failure in B cell maturation, resulting in antibody deficiency and increased susceptibility to infections. Patients with XLA are at risk of severe disease with infections with Campylobacter and closely related Helicobacter species and warrant treatment with close follow up given risk of recurrence. Method We present follow up of two 5-year-old fraternal twins with XLA who were diagnosed with C. upsaliensis and H. canis respectively via microbial cell-free DNA (mcfDNA) and underwent successful treatment with multi-drug antimicrobial therapy with 12 months of follow-up. Results Patient #1 was diagnosed with XLA at 11 months of age. At 3 years of age, he presented with fever and diarrhea, with stool cultures that grew C. jejuni. Despite treatment with azithromycin, his symptoms persisted and repeat stool cultures grew C. upsaliensis. Testing via mcfDNA confirmed C. upsaliensis. Patient #2 was diagnosed with XLA at 12 months of age. He developed fever, erythema nodosum (EN) like lesions and arthritis at 3.5 years old. Given his twin's diagnosis of Campylobacter sp. enteritis, he was given a presumptive diagnosis of Campylobacter reactive arthritis and EN. Despite treatment with Naprosyn and 14 days of azithromycin, his symptoms persisted and stool PCR was positive for Campylobacter sp. mcfDNA testing confirmed C. upsaliensis and H.canis. Given failure of initial antimicrobial therapy, both boys were treated with a 4-week course of IV ertapenem, and oral ciprofloxacin and amoxicillin, and both developed neutropenia and concern for drug toxicity. Therapy was transitioned to triple drug therapy with oral doxycycline, ciprofloxacin and amoxicillin. Doxycycline was discontinued after 3 weeks due to patients' young age. Ciprofloxacin and amoxicillin were continued for 12 months. Both boys had complete resolution of symptoms after 12 months of therapy and remain without recurrence 10 weeks after discontinuation of antimicrobial therapy. Conclusion Physicians should be aware of the treatment challenges of chronic Campylobacter and Helicobacter infection in boys with XLA and other immunocompromised hosts. Successful treatment may require prolonged multi-drug antimicrobial therapy, with monitoring for drug toxicities. [ABSTRACT FROM AUTHOR]

Hypertestosteroneemia can be caused by a variety of diseases and drugs, some of which can cause male infertility. We report a case of spinal and bulbar muscular atrophy (SMBA) diagnosed by hypertestosteronemia during infertility treatment. The patient was a 28-year-old man. His wife had no cause of infertility, did not become pregnant after 10 cycles of timed-intercourse. His semen test pointed out insufficient semen volume and asthenozoospermia. Although varicocele surgery was performed at the neighboring general hospital, semen findings did not improve. Even though two cycles of intrauterine insemination (IUI) were performed, she did not become pregnant. The couple were introduced to our clinic in November 2019. Semen findings at the first visit were same as first time. Serum hormone levels were LH 12.0 mIU / mL, FSH 3.9 mIU / mL and total testosterone 19.47 ng / mL. The testicular volume was 13 ml on both sides. SHIM: 22 points, EHS: Grade 3; the erectile function was a slight decreased. Drug-induced hypertestosteroneemia was negative. Microscopic pituitary adenoma revealed at the general hospital, but no pituitary dysfunction. The examination was conducted at the local national hospital, and a high value of CK 621 IU / L was pointed out. SMBA was suspected and the patient visited the neurology department. Finally, he had an allele of 49 CAG repeats and SMBA was diagnosed with mild bulbar palsy, weakness of the extremities Even with 3 courses of IUI, she did not become pregnant and was scheduled for in vitro fertilization (IVF). At the same time as the start of IVF, the patient had a definitive diagnosis of SMBA and was scheduled for LHRH agonist treatment. Because LHRH agonists were predicted to exacerbate semen findings, we performed sperm freezing for the purpose of fertility preservation. In the initial treatment cycle of ovum pick-up, 11 oocytes were collected, and 7 mature oocytes were obtained. Five oocytes were fertilized by ICSI using frozen sperm, and four blastocysts were vitrified. After that, the second vitrified-warmed blastocyst transplantation led to pregnancy, and the pregnancy is currently ongoing. SMBA, also known as Kennedy's Disease, affects adult men aged 30-60 years. It is a slowly progressive neuromuscular disease that causes muscle weakness, muscle atrophy, and fasciculation due to degeneration of lower motor neurons. This is a genetic disorder of X-linked recessive inheritance. It is caused by a trinucleotide repeat expansion; >40 CAG repeats, in the androgen receptor gene located on the X chromosome. Patients are mildly desensitized to androgens, causing gynecomastia, testicular atrophy, and diminished fertility. It is also accompanied by mild hypertestosteroneemia. These findings must have been the same for this patient. This report is the world's first report of fertility-preserving sperm freezing in SMBA patients using ejaculated sperm, and is also the first report of ICSI-induced pregnancy in frozen sperm in SMBA patients. The effectiveness of ART was suggested for SMBA patients. Work supported by industry: no. [ABSTRACT FROM AUTHOR]

Epilepsy is common in Rett syndrome, an X-linked dominant disorder caused by mutations in the MECP2 gene, and in Rett-related disorders, such as MECP2 duplication. However, neither the longitudinal course of epilepsy nor the patterns of seizure onset and remission have been described in Rett syndrome and related conditions. The present study summarizes the findings of the Rett syndrome Natural History study. Participants with clinical Rett syndrome and those with MECP2 mutations without the clinical syndrome were recruited through the Rett Natural History study from 2006 to 2015. Clinical details were collected, and cumulative lifetime prevalence of epilepsy was determined using the Kaplan-Meier estimator. Risk factors for epilepsy were assessed using Cox proportional hazards models. Of 1205 participants enrolled in the study, 922 had classic Rett syndrome, and 778 of these were followed longitudinally for 3939 person-years. The diagnosis of atypical Rett syndrome with a severe clinical phenotype was associated with higher prevalence of epilepsy than those with classic Rett syndrome. While point prevalence of active seizures ranged from 30% to 44%, the estimated cumulative lifetime prevalence of epilepsy using Kaplan-Meier approached 90%. Specific MECP2 mutations were not significantly associated with either seizure prevalence or seizure severity. In contrast, many clinical features were associated with seizure prevalence; frequency of hospitalizations, inability to walk, bradykinesia, scoliosis, gastrostomy feeding, age of seizure onset, and late age of diagnosis were independently associated with higher odds of an individual having epilepsy. Aggressive behaviour was associated with lower odds. Three distinct patterns of seizure prevalence emerged in classic Rett syndrome, including those who did not have seizures throughout the study, those who had frequent relapse and remission, and those who had relentless seizures. Although 248 of those with classic Rett syndrome and a history of seizures were in terminal remission at last contact, only 74 (12% of those with a history of epilepsy) were seizure free and off anti-seizure medication. When studied longitudinally, point prevalence of active seizures is relatively low in Rett syndrome, although lifetime risk of epilepsy is higher than previously reported. While daily seizures are uncommon in Rett syndrome, prolonged remission is less common than in other causes of childhood onset epilepsy. Complete remission off anti-seizure medications is possible, but future efforts should be directed at determining what factors predict when withdrawal of medications in those who are seizure free is propitious. [ABSTRACT FROM AUTHOR]

Motivation: Exome sequencing studies have facilitated the detection of causal genetic variants in yet-unsolved Mendelian diseases. However, the identification of disease causal genes among a list of candidates in an exome sequencing study is still not fully settled, and it is often difficult to prioritize candidate genes for follow-up studies. The inheritance mode provides crucial information for understanding Mendelian diseases, but none of the existing gene prioritization tools fully utilize this information. Results: We examined the characteristics of Mendelian disease genes under different inheritance modes. The results suggest that Mendelian disease genes with autosomal dominant (AD) inheritance mode are more haploinsufficiency and de novo mutation sensitive, whereas those autosomal recessive (AR) genes have significantly more non-synonymous variants and regulatory transcript isoforms. In addition, the X-linked (XL) Mendelian disease genes have fewer non-synonymous and synonymous variants. As a result, we derived a new scoring system for prioritizing candidate genes for Mendelian diseases according to the inheritance mode. Our scoring system assigned to each annotated protein-coding gene (N¼18 859) three pathogenic scores according to the inheritance mode (AD, AR and XL). This inheritance mode-specific framework achieved higher accuracy (area under curve ¼0.84) in XL mode. Conclusion: The inheritance-mode specific pathogenicity prioritization (ISPP) outperformed other well-known methods including Haploinsufficiency, Recessive, Network centrality, Genic Intolerance, Gene Damage Index and Gene Constraint scores. This systematic study suggests that genes manifesting disease inheritance modes tend to have unique characteristics. [ABSTRACT FROM AUTHOR]

Aarskog-Scott syndrome and atopic dermatitis successfully treated with dupilumab: a casual presentation? Consequently, I FGD1 i gene mutations impair normal development of bones and other tissues, causing skeletal dysplasia.2 We describe a case of association between ASS and atopic dermatitis (AD), which was successfully treated with dupilumab. Use of the Numerical Rating Scale questionnaire was not feasible because of the patient's intellectual disability; the patient's parents completed the Family Dermatology Life Quality Index (FDLQI), which gave a score of 29, indicating severe AD. [Extracted from the article]

The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns. Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15, SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined. The overlap with other neurodegenerative disorders has been implied in a small number of reports, but not in larger disease series. This deficiency has been largely due to the lack of suitable high throughput techniques to investigate the genetic basis of disease, but the recent availability of next generation sequencing can facilitate the identification of disease-causing mutations even in extremely heterogeneous disorders. We investigated a series of 97 index cases with complex spastic paraplegia referred to a tertiary referral neurology centre in London for diagnosis or management. The mean age of onset was 16 years (range 3 to 39). The SPG11 gene was first analysed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of probands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia in the UK, with severe and progressive clinical features and other neurological manifestations, linked with magnetic resonance imaging defects. Given the high frequency of SPG11 mutations, we studied the autophagic response to starvation in eight affected SPG11 cases and control fibroblast cell lines, but in our restricted study we did not observe correlations between disease status and autophagic or lysosomal markers. In the remaining cases, next generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15 Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson's disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 2-year-old Chinese girl presented with severe X-linked hypohidrotic ectodermal dysplasia (XLHED), along with complications of hypohidrosis, respiratory infections and chronic eczema. It mentions XLHED as a hypohidrotic ectodermal dysplasia (HED) which is caused by mutations of the gene for ectodysplasin A (EDA) gene. It also states analysis of X-chromosome inactivation pattern and cDNA expression.

The article describes the case of a patient diagnosed with vacuoles, E1 enzyme, X-linked, antiinflammatory, somatic (VEXAS) syndrome. Topics covered include the medical history of the patient, the patient's favorable response to intravenous immunoglobulin and anti-IL17 therapy, and clinical implications of the case.

STUDY QUESTION: How do data in the 13th annual data collection (Data XIII) of the European Society of Human Reproduction and Embryology (ESHRE) PGD Consortium compare with the cumulative data for collections I-XII? SUMMARY ANSWER: The 13th retrospective collection represents valuable data on PGD/PGS cycles, pregnancies and children: the main trend observed is the decrease in the routine implementation of PGS. WHAT IS KNOWN ALREADY: Since 1999, the PGD Consortium has collected, analysed and published 12 data sets and an overview of the first 10 years of data collections. STUDY DESIGN, SIZE, DURATION: Data were collected from each participating centre using a FileMaker Pro database (versions 5-11). Separate predesigned FileMaker Pro files were used for the cycles, pregnancies and baby records. The study documented cycles performed during the calendar year 2010 and follow-up of the pregnancies and babies born which resulted from these cycles (until October 2011). PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were submitted by 62 centres (full PGD Consortium members). The submitted data were thoroughly analysed to identify incomplete data entries and corrections were requested from the participating centres. Records remaining with incomplete or inconsistent data were excluded from the calculations. Corrections, calculations and tables were made by expert co-authors. MAIN RESULTS AND THE ROLE OF CHANCE: For data collection XIII, 62 centres reported data for 5780 cycles with oocyte retrieval (OR), along with details of the follow-up on 1503 pregnancies and 1152 babies born. A total of 1071 OR were reported for chromosomal abnormalities, 108 OR for sexing for X-linked diseases, 1574 OR for monogenic diseases, 2979 OR for preimplantation genetic screening and 48 OR for social sexing. LIMITATIONS, REASONS FOR CAUTION: The findings apply to the 62 participating centres and may not represent worldwide trends in PGD. WIDER IMPLICATIONS OF THE FINDINGS: The annual data collections provide an important resource for data mining and for following trends in PGD practice. STUDY FUNDING/COMPETING INTEREST(S): None. [ABSTRACT FROM AUTHOR]

Alport syndrome (AS) is a familial glomerular disorder resulting from mutations in the genes encoding several members of the type IV collagen protein family. Despite advances in molecular genetics, renal biopsy remains an important initial diagnostic tool. Histological diagnosis is challenging as features may be non-specific, particularly early in the disease course and in females with X-linked disease. We present three families for whom there was difficulty in correctly diagnosing AS or thin basement membrane nephropathy as a result of misinterpretation of non-specific and incomplete histology. We highlight the importance of electron microscopy and immunofluorescence in improving diagnostic yield and also the hazard of interpreting a descriptive histological term as a diagnostic label. Molecular genetic testing allows a definitive diagnosis to be made in index patients and at-risk family members. [ABSTRACT FROM PUBLISHER]

Background Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene. Deficiency of α-galactosidase A (α-Gal A) causes intracellular accumulations of globotriaosylceramide (GL-3) and related glycosphingolipids in all organs, including the kidney, often leading to end-stage renal failure. In women with Fabry disease, accumulation of GL-3 in the glomerular podocytes and other renal cells induces progressive, proteinuric nephropathy, but not as severe as in men. Enzyme replacement therapy (ERT) with recombinant α-Gal A reduces cellular GL-3 deposits in podocytes and tubular epithelial cells. We have previously shown that α-Gal A is delivered to these cells by different pathways involving different receptors. This study investigated the long-term changes in albuminuria, estimated glomerular filtration rate (eGFR) and urinary markers of both glomerular and tubular dysfunction in women with Fabry disease treated with ERT. Methods A retrospective, single centre, cohort study evaluated the long-term association between ERT, albuminuria and eGFR in 13 women with Fabry disease and mild renal involvement. In particular, we analysed the changes in the proteinuric profile, including the glomerular marker IgG, the tubular markers α1-microglobulin and retinol-binding protein (RBP), and the shared tubular and glomerular markers albumin and transferrin. Results ERT was associated with a significant reduction in albuminuria and a relatively stable eGFR. The decrease in albuminuria was paralleled by a decrease in both glomerular and tubular urine protein markers. Conclusions The data indicate that long-term ERT is associated with a reduction in albuminuria and glomerular and tubular urinary protein markers in women with Fabry disease and mild renal manifestations. [ABSTRACT FROM PUBLISHER]

STUDY QUESTION What is the burden of X chromosome mosaicism in the occurrence of spontaneous menarche (SM) in Turner syndrome (TS)? SUMMARY ANSWER SM was significantly associated with X chromosome mosaicism in the TS patients; a mosaicism with around 10% euploid cell line may predict spontaneous pubertal development when determined by molecular-cytogenetic techniques on uncultivated tissues. WHAT IS KNOWN ALREADY Spontaneous puberty can be observed in a minority of patients with TS, more frequently, but not exclusively, in those with a high level of 46,XX/45,X mosaicism at standard karyotype. The genetic mechanisms contributing to ovarian function in TS patients are still not determined. However, submicroscopic X-linked and autosomal copy number variations (CNVs) have recently emerged as an important genetic risk category for premature ovarian insufficiency and may be involved in modulating the TS ovarian phenotype. STUDY DESIGN, SIZE, DURATION A group of 40 patients with a diagnosis of TS at conventional karyotyping participated in the study; 6 patients had SM and 34 patients had primary amenorrhoea (PA). All clinical data and the patients’ DNA samples were collected over the years at a single paediatric clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS The patients' samples were used to perform both genetic (Copy Number Assay) and molecular-cytogenetic (array-CGH and iFISH, interphase-FISH) analyses in order to evaluate the X chromosome mosaicism rate and to detect possible rare CNVs of genes with a known or predicted role in female fertility. MAIN RESULTS AND THE ROLE OF CHANCE All TS patients showed variable percentages of the 46,XX lineage, but these percentages were higher in the SM group (P < 0.01). A mosaicism around 10% for the euploid cell line may predict spontaneous pubertal development when determined by molecular-cytogenetic techniques performed in uncultivated tissues. A few CNVs involving autosomal and X-linked ovary-related loci were identified by array-CGH analysis and confirmed by real-time quantitative PCR, including a BMP15 gene duplication at Xp11.22, a deletion interrupting the PAPPA gene at 9q33.1, and an intragenic duplication involving the PDE8A gene at 15q25.3. LIMITATIONS, REASONS FOR CAUTION This is a pilot study on a relatively small sample size and confirmation in larger TS cohorts may be required. The ovarian tissue could not be studied in any patients and in a subgroup of patients, the mosaicism was estimated in tissues of different embryonic origin. WIDER IMPLICATIONS OF THE FINDINGS The combined determination of X chromosome mosaicism by molecular and molecular-cytogenetic techniques may become useful for the prediction of SM in TS. The detection of CNVs in both X-linked and autosomal ovary-related genes further suggests gene dosage as a relevant mechanism contributing to the ovarian phenotype of TS patients. These CNVs may pinpoint novel candidates relevant to female fertility and generate further insights into the mechanisms contributing to ovarian function. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Telethon Foundation (grant no: GGP09126 to L.P.), the Italian Ministry of the University and Research (grant number: 2006065999 to P.F.) and a Ministry of Health grant ‘Ricerca Corrente’ to IRCCS Istituto Auxologico Italiano (grant number: 08C704-2006). The authors have no conflict of interest to declare. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a ‘halo’ of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is an X-linked disorder of glycosphingolipid catabolism resulting in the accumulation of glycolipids including globotriaosylceramide in cells of various tissues resulting in end-organ manifestations. Initially, FD is typically characterized by angiokeratoma and recurrent episodes of neuropathic pain in the extremities occurring during childhood or adolescence. Most affected patients also exhibit a decreased ability to sweat. Later in life, FD results in left ventricular hypertrophy, proteinuria, renal failure and stroke. These later disease manifestations are non-specific and also common in diabetes, hypertension and atheromatosis and thus for most practitioners do not point into the direction of FD. As a consequence, FD is under-diagnosed and screening of high-risk groups is important for case finding, as is a thorough pedigree analysis of affected patients. In the nephrology clinic, we suggest to screen patients for FD when there is unexplained chronic kidney disease in males younger than 50 years and females of any age. In men, this can be performed by measuring α-galactosidase A activity in plasma, white blood cells or dried blood spots. In women, mutation analysis is necessary, as enzyme measurement alone could miss over one-third of female Fabry patients. A multidisciplinary team should closely monitor all known Fabry patients, with the nephrologist screening kidney impairment (glomerular filtration rate and proteinuria) on a regular basis. Transplanted Fabry patients have a higher mortality than the regular transplant population, but have acceptable outcomes, compared with Fabry patients remaining on dialysis. It is unclear whether enzyme replacement therapy (ERT) prevents deterioration of kidney function. In view of the lack of compelling evidence for ERT, and the low likelihood that a sufficiently powered randomized controlled trial on this topic will be performed, data of all patients with FD should be collected in a central registry. [ABSTRACT FROM PUBLISHER]

Oxidative damage is a pivotal aetiopathogenic factor in X-linked adrenoleukodystrophy. This is a neurometabolic disease characterized by the accumulation of very-long-chain fatty acids owing to the loss of function of the peroxisomal transporter Abcd1. Here, we used the X-linked adrenoleukodystrophy mouse model and patient’s fibroblasts to detect malfunctioning of the ubiquitin–proteasome system resulting from the accumulation of oxidatively modified proteins, some involved in bioenergetic metabolism. Furthermore, the immunoproteasome machinery appears upregulated in response to oxidative stress, in the absence of overt inflammation. i-Proteasomes are recruited to mitochondria when fibroblasts are exposed to an excess of very-long-chain fatty acids in response to oxidative stress. Antioxidant treatment regulates proteasome expression, prevents i-proteasome induction and translocation of i-proteasomes to mitochondria. Our findings support a key role of i-proteasomes in quality control in mitochondria during oxidative damage in X-linked adrenoleukodystrophy, and perhaps in other neurodegenerative conditions with similar pathogeneses. [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency disorders (CVID) are a group of heterogeneous conditions that have in common primary failure of B cell function, although numerous T cell abnormalities have been described, including reduced proliferative response and reduced regulatory T cells. This study compared the T cell phenotype of CVID patients subdivided into clinical phenotypes as well as patients with partial antibody deficiencies [immunoglobulin (Ig)G subclass deficiency and selective IgA deficiency], X-linked agammaglobulinaemia (XLA) and healthy and disease controls. Absolute numbers of T cell subpopulations were measured by four-colour flow cytometry: naive T cells, central and effector memory and terminally differentiated (TEM) T cells, using CD45RA and CCR7 expression. Early, intermediate and late differentiation status of T cells was measured by CD27/CD28 expression. Putative follicular T cells, recent thymic emigrants and regulatory T cells were also assessed. Significant reduction in naive CD4 T cells, with reduced total CD4 and recent thymic emigrant numbers, was observed in CVID patients, most pronounced in those with autoimmune cytopenias or polyclonal lymphoproliferation. These findings suggest a lack of replenishment by new thymically derived cells. CD8 naive T cells were reduced in CVID patients, most significantly in the autoimmune cytopenia subgroup. There was a reduction in early differentiated CD4 and CD8 T cells and increased CD8 TEM in the CVID patients, particularly autoimmune cytopenia and polyclonal lymphoproliferation subgroups, suggesting a more activated T cell phenotype, due perhaps to an antigen-driven process. XLA patients had significantly reduced putative follicular T cells, which may depend on B cells for survival, while no significant alterations were observed in the T cells of those with IgG subclass deficiency or selective IgA deficiency. [ABSTRACT FROM AUTHOR]

DAX1/NR0B1 mutations are responsible for X-linked congenital adrenal hypoplasia (AHC) associated with hypogonadotropic hypogonadism (HH). Few data are available concerning testicular function and fertility in men with DAX1 mutations. Azoospermia as well as failure of gonadotrophin treatment have been reported. We induced spermatogenesis in a patient who has a DAX1 mutation (c.1210C>T), leading to a stop codon in position 404 (p.Gln404X). His endocrine testing revealed a low testosterone level at 1.2 nmol/l (N: 12–40) with low FSH and LH levels at 2.1 IU/l (N: 1–5 IU/l) and 0.1 IU/l (N: 1–4 IU/l), respectively. Baseline semen analysis revealed azoospermia. Menotropin (Menopur®:150 IU, three times weekly) and human chorionic gonadotrophin (1500 IU, twice weekly) were used. After 20 months of treatment, as azoospermia persisted, bilateral multiple site testicular biopsies were performed. Histology revealed severe hypospermatogenesis. Rare spermatozoa were extracted from the right posterior fragment and ICSI was performed. Four embryos were obtained and, after a frozen–thawed single-embryo transfer, the patient's wife became pregnant and gave birth to a healthy boy. We report the first case of paternity after TESE–ICSI in a patient with DAX1 mutation, giving potential hope to these patients to father non-affected children. Furthermore, this case illustrates the fact that patients with X-linked AHC have a primary testicular defect in addition to HH. [ABSTRACT FROM PUBLISHER]

A correction to the article "Higher prevalence of non-skeletal comorbidity related to X-linked hypophosphataemia: a UK parallel cohort study using CPRD" is presented.

The article presents a case study of a 16-year-old boy with a history of recurrent burning limb pain which was misdiagnosed as complex regional pain syndrome. A suspicion of Fabry disease (FD) was made after clinical history and findings including acroparesthesia, abdominal pain, and delayed puberty. The patient undergone enzyme replacement therapy, resulting to good pain management and improved quality of life.

The article presents a case study of a 2-day-old girl was examined for red scars on her face observed immediately after a normal vaginal delivery. His physical examination bright red scar-like linear plaques were visible on the patient's face and microphthalmia with linear skin defects syndrome which is an X-linked dominant disorder. His examination revealed that in addition to the lesions, the child had microphthalmia.

The article presents a case study of a patient who was diagnosed with the X-linked reticulate pigmentary disorder (XLPDR). Details regarding his diagnostic proceedings are presented, which included genetic and immunological tests. Topics discussed include details regarding the disease, presentation of skin manifestations in the patient and the findings in the case.