Rare X-linked Genetic Disorder Research Articles

Clinical and genetic characterization of three families with Nance-Horan syndrome caused by NHS gene mutations

Objective: To explore the clinical phenotypes and pathogenic gene variation characteristics of three Chinese Han ethnic families affected by Nance-Horan syndrome, a rare X-linked genetic disorder. Methods: A pedigree investigation study was conducted at the First Affiliated Hospital of Zhengzhou University, collecting clinical data from three Chinese Han families with Nance-Horan syndrome between February 2009 and September 2018. Detailed family histories, comprehensive ophthalmological and systemic examinations were documented. Pedigree charts were created, and genetic inheritance patterns were analyzed to preliminarily diagnose the probands and other affected individuals. Genomic DNA was extracted from peripheral blood samples of family members, and next-generation sequencing was used to screen for target gene variations, which were confirmed by Sanger sequencing. Pathogenicity of the genetic variants and their impact on three-dimensional protein structure were analyzed using MutationTaster and computer-aided protein modeling. Results: In Family 1, there are 5 patients, including 4 females (aged 42, 37, 9 and 7) and 1 males (aged 12). In Family 2, there are 5 patients, including 3 females (aged 54, 32 and 16) and 2 males (aged 26 and 9). In Family 3, there are 8 patients, including 5 females (aged 69, 42, 37, 35 and 14) and 3 males (aged 10, 7 and 4). All probands in the three families exhibited nuclear cataracts with typical congenital hereditary cataract features, but no noticeable abnormalities in facial appearance or teeth. Next-generation sequencing identified new variation sites in the NHS gene, specifically c.2519_2520del, exon3del, and c.3847C>T. These variations included nonsense mutation p.(Ser840*), exon deletion p.(?), and nonsense mutation p.(Gln1283*). Combined clinical and genetic sequencing results confirmed X-linked Nance-Horan syndrome in all three families. Bioinformatics analysis indicated these variation sites were pathogenic and resulted in abnormal three-dimensional protein structures, likely being the main cause of Nance-Horan syndrome. Conclusion: The majority of patients from the three Nance-Horan syndrome families studied were affected by congenital hereditary cataracts characterized by nuclear opacities.The NHS gene variations c.2519_2520del, exon3del, and c.3847C>T are newly identified pathogenic sites in Nance-Horan syndrome, reported for the first time across three different families.

Overhauling dental implications in a child with rare craniofrontonasal syndrome: a case report

Craniofrontonasal syndrome is an extremely rare X-linked dominant genetic disorder characterized by features such as hypertelorism, craniosynostosis, ocular anomalies, a bifid nasal tip, and longitudinal ridging with splitting of the nails. Heterozygous females are more severely affected, presenting frontonasal dysplasia and coronal craniosynostosis (fusion of the coronal sutures), while males typically only exhibit hypertelorism. This case report describes the dental management of a 9-year-old female with craniofrontonasal syndrome who was referred to the department of paediatric and preventive dentistry for pain in the lower right and left back tooth region. The patient exhibited a clinical spectrum including microcephaly, short neck, axillary pterygium, clinodactyly of the toes, longitudinal ridging with split nails, pectus excavatum, and underdeveloped female genitalia. Extraoral examination revealed hypertelorism, flat nasal bridge, low-set ears, strabismus, antimongoloid slant, and an indistinct philtrum. Intraoral examination showed a high palatal vault, crowding of the upper and lower arches during the mixed dentition period, multiple dental caries, and poor oral hygiene. An orthopantomogram confirmed delayed dental development. Dental treatment was carried out on a dental chair system using adequate behaviour management techniques with short appointments, keeping in mind the reduced cooperative ability of the child. The importance of this report stems from the limited dental literature available on the syndrome. Preventive measures along with home care instructions were emphasized to support professional care.

Airway management of a patient with coffin-lowry syndrome: a case report

Coffin-Lowry Syndrome (CLS) is a rare X-linked genetic disorder characterized by growth delays, facial dysmorphisms, and intellectual disabilities. Currently, there are limited published case reports regarding the anesthetic management of patients with CLS. Managing anesthesia for CLS patients can be complex due to difficult airway management. In this case report, we present a patient with CLS who underwent surgical intervention, highlighting the anesthetic considerations encountered throughout the perioperative period. We aim to summarize the difficulties involved in anesthetic management of rare conditions like CLS to improve clinical outcomes for affected individuals.

Clinical Characteristics, Developmental Trajectory, and Caregiver Burden of Patients With Creatine Transporter Deficiency (SLC6A8).

Creatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and trajectory of patients with CTD and the impact of the disease on caregivers to identify relevant endpoints for future therapeutic trials. As part of a French National Research Program, patients with CTD were included based on (1) a pathogenic SLC6A8 variant and (2) ID and/or autism spectrum disorder. Families and patients were referred by the physician who ordered the genetic analysis through Reference Centers of ID from rare causes and inherited metabolic diseases. After we informed the patients and their parents/guardians about the study, all of them gave written consent and were included. A control group of age-matched and sex-matched patients with Fragile X syndrome was also included. Physical examination, neuropsychological assessments, and caregiver impact were assessed. All data were analyzed using R software. Thirty-one patients (27 male, 4 female) were included (25/31 aged 18 years or younger). Most of the patients (71%) had symptoms at <24 months of age. The mean age at diagnosis was 6.5 years. Epilepsy occurred in 45% (mean age at onset: 8 years). Early-onset behavioral disorder occurred in 82%. Developmental trajectory was consistently delayed (fine and gross motor skills, language, and communication/sociability). Half of the patients with CTD had axial hypotonia during the first year of life. All patients were able to walk without help, but 7/31 had ataxia and only 14/31 could walk tandem gait. Most of them had abnormal fine motor skills (27/31), and most of them had language impairment (30/31), but 12/23 male patients (52.2%) completed the Peabody Picture Vocabulary Test. Approximately half (14/31) had slender build. Most of them needed nursing care (20/31), generally 1-4 h/d. Adaptive assessment (Vineland) confirmed that male patients with CTD had moderate-to-severe ID. Most caregivers (79%) were at risk of burnout, as shown by Caregiver Burden Inventory (CBI) > 36 (significantly higher than for patients with Fragile X syndrome) with a high burden of time dependence. In addition to clinical endpoints, such as the assessment of epilepsy and the developmental trajectory of the patient, the Vineland scale, PPVT5, and CBI are of particular interest as outcome measures for future trials. ANSM Registration Number 2010-A00327-32.

Pegunigalsidase alfa: a novel, pegylated recombinant alpha-galactosidase enzyme for the treatment of Fabry disease.

Fabry disease, a rare X-linked genetic disorder, results from pathogenic variants in GLA, leading to deficient lysosomal α-galactosidase A enzyme activity and multi-organ manifestations. Since 2001, enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta, has been the mainstay treatment, albeit with limitations such as rapid clearance and immunogenicity. Pegunigalsidase alfa, a novel PEGylated recombinant alpha-galactosidase, offers promise as an alternative. Produced in plant cells, pegunigalsidase alfa exhibits enhanced stability, prolonged half-life, and reduced immunogenicity due to pegylation. A phase 1/2 clinical trial demonstrated Gb3 clearance from renal capillary endothelial cells and its 48-month extension study revealed notable outcomes in renal function preservation. Three phase 3 clinical trials (BRIDGE, BRIGHT, and BALANCE) have shown favorable efficacy and safety profile, although caution is warranted in interpreting the results of BRIDGE and BRIGHT which lacked control groups. In BALANCE, the pivotal phase 3 trial comparing pegunigalsidase alfa with agalsidase beta, an intention-to-treat analysis of the eGFR decline over 2years showed that the intergroup difference [95%confidence interval] in the median slope was -0.36mL/min/1.73 m2/year [-2.44; 1.73]. The confidence interval had a lower limit above the prespecified value of -3mL/min/1.73 m2/year and included zero. Despite challenges such as occasional hypersensitivity reactions and immune-complex-mediated glomerulonephritis, pegunigalsidase alfa approval by the European Medicines Agency and the Food and Drug Administration represents a significant addition to Fabry disease therapeutic landscape providing an option for patients in whom enzyme replacement therapy with current formulations is poorly tolerated or poorly effective.

The Analysis of Hematological Parameters CBC, ABO, NLR, and APTT and Its Implications on Haemophilic Patients with Low Bone Mineral Density

Background: Haemophilia is a rare X-linked recessive genetic disorder characterized by the absence or deficiency of factor VIII (haemophilia A) or factor IX (haemophilia B). The current study aimed to assess some hematological factors in hemophilic patients with low bone mineral density (BMD). Objective: The study was carried out on Iraqi patients with hemophilia at the National Center of Hematology, Mustansiriyah University. Method: Sixty-eight male patients were involved in this study, with ages ranging from (14 to 53) years. Along with the patient group, 18 healthy subjects with matched age and gender were involved as the control group. Various hematological parameters were determined in the samples of healthy and patient subjects. Results: The results found that; only 39.7% of patients have positive DEXA scan characterized by low BMD (abbreviated as DX+) and 60.3 % with normal BMD (abbreviated as DX0), and reveal non-significant in ABO system distribution; all RBCs indices, WBC, prothrombin time, and platelets count (PLT) in patients (DX+, DX0) and control groups, higher NLR ratio was greater in patients in the DX+ group than in the DX0 and control groups; furthermore Activated-partial thromboplastin time (APTT) in DX+ and DX0 groups of patients are significantly (P ? 0.0001) higher than in control group. Conclusion: the increase in neutrophils-lymphocytes ratio (NLR) and prolonged of APTT may be a marker that increases the risk of low bone density development in hemophilic patients.

Nonsense-mediated mRNA decay affects hyperactive root formation in oculo-facio-cardio-dental syndrome via up-frameshift protein 1

ObjectivesOculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked genetic disorder caused by mutations in the BCL6 co-repressor (BCOR) and is mainly characterized by radiculomegaly (elongated dental roots). All BCOR mutations reported to date have been associated with premature termination codons, indicating that nonsense-mediated mRNA decay (NMD) might play a vital role in the pathogenesis of OFCD syndrome. However, the molecular mechanisms underlying NMD remain unclear. In this study, we investigated the involvement of up-frameshift protein 1 (UPF1), which plays a central role in NMD, in the hyperactive root formation caused by BCOR mutations. MethodsPeriodontal ligament cells, isolated from a Japanese woman with a c.3668delC frameshift mutation in BCOR, and primary human periodontal ligament fibroblasts (HPdLFs) were used for an RNA immunoprecipitation assay to confirm the binding of UPF1 to mutated BCOR. Additionally, the effects of UPF1 on the BCOR transcription levels and corresponding gene expression were determined by performing relative quantitative real-time polymerase chain reactions. ResultsRNA immunoprecipitation revealed that UPF1 binds to exon 9 of mutated BCOR. Additionally, UPF1 knockdown via siRNA upregulated the transcription of BCOR, whereas overexpression of wild-type and mutated BCOR with the same frameshift mutation in HPdLFs altered bone morphogenetic protein 2 (BMP2) expression. ConclusionsOur findings indicate that BCOR mutations regulate the transcription of BCOR via UPF1, which may in turn regulate the expression of BMP2. NMD, caused by a c.3668delC mutation, potentially leads to an OFCD syndrome phenotype, including elongated dental roots.

Incontinentia Pigmenti in a 3-Year-Old Female: A Case Report

Incontinentia Pigmenti (IP), also known as Bloch-Sulzberger syndrome, is a rare X-linked genetic disorder characterized by a distinctive cutaneous manifestation along with variable systemic involvement. We present a case of a 3-month-old female infant diagnosed with IP, highlighting the clinical features, diagnostic approach, and management strategies. Early recognition and multidisciplinary care are crucial for optimizing outcomes in affected infants.

Effect of pharmacological heart failure drugs and gene therapy on Danon's cardiomyopathy

Danon disease is a rare X-linked genetic disease resulting from LAMP2 mutations leading to defective lysosomal function. Heart failure is the main causes of morbidity and mortality. Mice with an LAMP2-exon-6-deletion (L2Δ6), develop cardiac hypertrophy followed by dilated cardiomyopathy, in association with accumulation of autophagosomes, fibrosis and oxidative stress. We investigated the effect of drugs used to treat heart failure and of LAMP2 gene therapy on the phenotype, molecular markers and ROS in LAMP2 cardiomyopathy. L2Δ6 mice were treated with Angiotensin II, Ramipril, Metoprolol or Spironolactone. Gene therapy was delivered by IP injection of Adeno-associated-virus (AAV9) -LAMP2 vector to neonates (“AAVLAMP2-Prevention”), or at 15 weeks of age (“AAVLAMP2-Treatment”). Angiotensin II markedly aggravated the cardiac phenotype. Ramipril and Spironolactone were effective in attenuating left ventricular hypertrophy and preserving the systolic function. Cardiac protection was associated with decreased autophagosome accumulation, reduced fibrosis and oxidative stress. Gene therapy effectively attenuated autophagosome accumulation and ROS in L2Δ6 hearts, lowering troponin release to nearly normal levels. AAVLAMP2-Prevention protected against systolic dysfunction and decreased hypertrophy. AAVLAMP2-Treatment prevented ventricular dilatation and dysfunction but had no effect on wall thickness. We conclude that RAAS inhibitors are highly effective against cardiomyopathy progression in an experimental mouse model of Danon's and shall be considered in human patients for this purpose until novel therapies become clinically available.

The Relationship Between Participant-Reported Energy Levels &amp; Energy Expenditure &amp; Sleep Among Individuals With Barth Syndrome

Abstract Date Presented 04/22/2023 What is 'Barth Tired'? Barth syndrome (BTHS) is a rare X-linked genetic disorder in which exercise intolerance is common because of early fatigue. Energy expenditure and sleep information are tracked for 14 days using an activity tracker, and participants logtheir perceived levels of fatigue using a phone app. We saw significant correlations between energy expenditure and perceived levels of fatigue in adults with BTHS and between sleep time and perceived levels of fatigue in children with BTHS. Primary Author and Speaker: Virginia W. Chu Additional Authors and Speakers: Sanamtha Payne, Mackenzie Hunter Contributing Authors: Stacey Reynolds

#2635 ASSOCIATION BETWEEN PLASMA LYSO-GB3 LEVELS AND BONE MINERAL DENSITY IN PATIENTS WITH FABRY DISEASE

Abstract Background and Aims Fabry disease is a rare X-linked genetic disorder that contributes to various clinical manifestations including cardiac hypertrophy, renal dysfunction, cerebrovascular disease, angiokeratoma, and anhidrosis. Several previous reports showed that male patients with Fabry disease had decreased bone mineral density (BMD). However, the association of BMD with clinical characteristics and biomarkers of organ damage in patients with Fabry disease has not been sufficiently studied. Therefore, we aimed to investigate their associations in patients with Fabry disease. Method Patients with Fabry disease who attended our hospital from January 2008 to June 2021 were included in this study. Patients without enough clinical and laboratory data were excluded from the present study. The remaining fifteen patients were assessed in this study. We examined clinical characteristics, biomarkers including blood globotriaosylsphingosine (lyso-Gb3) levels, and BMD, and compared them between male and female patients. We measured the lumbar spine and femoral BMD by dual-energy bone X-ray absorptiometry and calculated the Z-score. Furthermore, we also examined ΔBMD, defined as the two-year change in the Z-score, for ten patients who underwent BMD measurement before and after starting ERT. Because two patients already had received ERT, two did not undergo BMD measurement, and one took an anti-osteoporotic agent, they were excluded from the analysis. Results Both lumbar spine BMD and femoral BMD decreased in male patients, while they were preserved in female patients (lumbar spine Z-score: -1.9 ± 2.0 versus 0.8 ± 0.8, p &amp;lt; 0.05; femoral Z-score: -1.0 ± 1.4 versus 0.6 ± 0.6, p &amp;lt; 0.05) among all the study patients. Lumbar spine and femoral BMD showed a significantly negative correlation with blood lyso-Gb3 levels. Moreover, blood lyso-Gb3 levels were significantly correlated with the lumbar spine BMD (r = -0.92; p &amp;lt; 0.01) and femoral BMD (r = -0.91; p &amp;lt; 0.01) in male patients. On the other hand, there was no significant correlation of blood lyso-Gb3 levels with the lumbar spine BMD (r = 0.66, p = 0.18) and femoral BMD (r = 0.11; p = 0.99) in female patients. After starting ERT, blood lyso-Gb3 levels were significantly reduced in both male and female patients. The lumbar spine ΔBMD in male patients improved whereas that in female patients remained unchanged despite no changes in kidney function and serum calcium and phosphate levels. Conclusion Our findings suggested that lumbar spine BMD and femoral BMD decreased in male patients with Fabry disease possibly due to the deposition of lyso-Gb3 in bone tissue and ERT could improve BMD in these patients.

Reduction in mRNA Expression of the Neutrophil Chemoattract Factor CXCL1 in Pseudomonas aeruginosa Treated Barth Syndrome B Lymphoblasts.

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

BRUNNER SYNDROME: FROM GENETICS TO PSYCHIATRY - CASE REPORT

IntroductionMonoaminergic neurotransmitters affect motor control, emotions and cognitive functions. Their relative abundance depends on the action of monoamine oxidase A (MAOA) which catalyses their degradation into inactive metabolites. Brunner syndrome is a rare chromosome X-linked recessive inheritance genetic disorder, which causes loss of function of the MAOA gene, leading to a relative increase in monoamines in affected individuals (typically males). It manifests with moderate intellectual developmental disturbance associated with maladaptive externalising behaviours, low frustration tolerance and marked impulsivity.ObjectivesTo present a clinical case of patient diagnosed with Brunner Syndrome presenting with suicidal and homicidal ideation and to discuss it based on a non-systematic review of the literature.MethodsCase report and non-systematic review of the literature.Results: Case ReportMale born with neonatal asphyxia that consequently presented developmental retardation characterised by learning difficulties and emotional dysregulation. At 18 years of age, he began follow-up in Psychiatry due to self-injurious behaviours and several reactive suicide attempts (SA), being diagnosed with Intellectual Disability. At 22, he was hospitalised due to reactive depression, being discharged doing well with valproate, fluoxetine and olanzapine. Shortly after, he was arrested (aged 23-28) for attempted murder followed by SA. During imprisonment, he was diagnosed with Brunner’s Syndrome after his younger brother diagnosis. At 31, he was hospitalised for suicidal and homicidal ideation, revealing high impulsiveness and low frustration tolerance, and was discharged with compulsory psychiatric treatment. Three weeks later he was again hospitalised for symptoms recurrence having improved on Sertraline 50mg and Aripiprazole 400mg monthly.DiscussionAlthough scarce, the available evidence suggests that dietary modifications and the use of selective serotonin reuptake inhibitors may improve behaviour, reduce serotoninergic symptoms and possibly reverse some neurochemical abnormalities.ConclusionsBrunner syndrome is a rare genetic disorder with neuropsychiatric manifestations, whose course, treatment and prognosis are currently poorly known. Thus, the current treatment is empirical and further studies are needed.Disclosure of InterestNone Declared

Ganaxolone in seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: a profile of its use in the USA

Ganaxolone (ZTALMY®), a synthetic neuroactive steroid that acts as a positive allosteric modulator of the synaptic and extrasynaptic gamma-aminobutyric acid (GABA)A receptor, is an effective and well tolerated, orally-administered adjunct to existing antiseizure treatments in patients 2 years of age or older with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD)-associated seizures. CDD (a rare X-linked genetic disorder) is a severe developmental epileptic encephalopathy with onset in early infancy. In the randomized, double-blind, phase 3 Marigold trial, adjunctive ganaxolone significantly reduced the 28-day major motor seizure frequency from baseline compared with placebo in patients with CDD-associated refractory epilepsy. Preliminary results from the Marigold open-label extension suggest that the clinical benefits of ganaxolone in patients with CDD are maintained longer term. Ganaxolone is generally well tolerated; somnolence is the most frequent adverse reaction.

Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome

Hunter syndrome is a rare x-linked recessive genetic disorder that affects lysosomal metabolism due to deficiency of iduronate-2-sulfatase (IDS), with subsequent accumulation of glycosaminoglycans heparan and dermatan sulfates (GAG). Enzyme replacement therapy is the only FDA-approved remedy and is an expensive life-time treatment that alleviates some symptoms of the disease without neurocognitive benefit. We previously reported successful treatment in a mouse model of mucopolysaccharidosis type II (MPS II) using adeno-associated viral vector serotype 9 encoding human IDS (AAV9.hIDS) via intracerebroventricular injection. As a less invasive and more straightforward procedure, here we report intravenously administered AAV9.hIDS in a mouse model of MPS II. In animals administered 1.5 × 1012 vg of AAV9.hIDS at 2 months of age, we observed supraphysiological levels of IDS enzyme activity in the circulation (up to 9100-fold higher than wild-type), in the tested peripheral organs (up to 560-fold higher than wild-type), but only 4% to 50% of wild type levels in the CNS. GAG levels were normalized on both sides of the blood-brain-barrier (BBB) in most of tissues tested. Despite low levels of the IDS observed in the CNS, this treatment prevented neurocognitive decline as shown by testing in the Barnes maze and by fear conditioning. This study demonstrates that a single dose of IV-administered AAV9.hIDS may be an effective and non-invasive procedure to treat MPS II that benefits both sides of the BBB, with implications for potential use of IV-administered AAV9 for other neuronopathic lysosomal diseases.

Diagnosis of cardiovascular involvement in Fabry disease

Fabry disease is a rare X-linked genetic disorder, caused by partial or total loss of function of the lysosomal enzyme α-galactosidase A that induces glycosphingolipid accumulation in various organs and tissues, modifying their structure and function. Cardiovascular involvement in classic and late onset forms has emerged to be a major determinant of prognosis. In recent years, a constant evolution in imaging techniques and their mindful application has led to interesting results in the diagnostic workup, progressively reducing time required to recognize early signs of this disease. Owing to the growing awareness for diagnostic screening and the efficacy of the many therapeutic options currently available, the clinical history of Fabry patients has changed during the last decades. Therefore, an early diagnosis of Fabry disease and especially of cardiac involvement is essential to promptly adopt an adequate therapy.

A Case Report of Norrie Disease with Congenital Sensorineural Hearing Loss

Norrie Disease (ND) is a rare X-linked recessive genetic disorder caused by mutations in the Norrie disease protein (NDP) gene on the X chromosome. This disorder leads to congenital or neonatal blindness, progressive hearing loss in adolescence, and cognitive or behavioral problems. Although hearing loss is a characteristic feature of ND, it is often overlooked due to the prominence of ocular symptoms. This article presents a rare case of ND in a 3-month-old boy who failed the universal newborn hearing screening (UNHS) bilaterally, further audiological evaluation revealed bilateral sensorineural hearing loss. Suggests that patients with ND may be born with congenital hearing loss, earlier than the previous reports. Addressing hearing loss at an early stage can help minimize the compounding effect on cognitive functioning and improve overall mental well-being.

Barth Syndrome: Psychosocial Impact and Quality of Life Assessment.

Barth syndrome (BTHS) is a rare X-linked genetic disease that affects multiple systems and leads to complex clinical manifestations. Although a considerable amount of research has focused on the physical aspects of the disease, less has focused on the psychosocial impact and quality of life (QoL) in BTHS. The current study investigated caregiver- (n = 10) and self-reported (n = 16) psychological well-being and QoL in a cohort of BTHS-affected patients and families. Participants completed the depression and anxiety components of the Patient-Reported Outcomes Information System (PROMIS) Short Form 8A and Health-related quality of life (HRQoL) surveys at enrollment and again during a follow-up period ranging from 6 to 36 months after baseline. Quality of life changed significantly over time and the various domains with some improvement and some decline. Among the available caregiver-patient dyad data, there was a trend toward discordance between caregiver and self-reported outcomes. Most notably, patients reported improvement in HRQoL, while caregivers reported declines. This suggests that there may be differences in perceived quality of life between the patients and parents, though our study is limited by small sample size. Our study provides valuable insights into the impacts of psychosocial and mental health aspects of BTHS. Implications of these findings include incorporating longitudinal assessment of QoL and screening for psychological symptoms in BTHS care to identify interventions that may drastically impact health status and the course of the disease.

Hypohidrotic Ectodermal Dysplasia: a rare inherited multisystem disorder

Hypohidrotic ectodermal dysplasia (HED), also known as Christ-Siemens-Touraine syndrome, is a rare X-linked genetic disorder characterized by the faulty development of the ectodermal structures, resulting in most notably anhydrosis/ hypohidrosis, hypotrichosis and hypodontia. Here, we report clinical presentation of a HED case. A female child aged 8 years was brought with complaints of high grade fever along with upper respiratory tract illness symptoms. She also had recurrent episodes of unexplained hyperpyrexia and thirst. Physical examination revealed characteristic appearance which aided in arriving at a diagnosis. Diagnosing this disorder in early life prevents mortality which is high especially during neonatal period. Therefore, it is essential for the treating clinician to have basic knowledge on the clinical presentations as well as complications of this specific genetic disease so that it is not missed. It is rare to see a classical case of hypohidrotic ectodermal dysplasia in female children with typical phenotypic features hence, this case report is presented.

Tafazzin deficiency attenuates anti-cluster of differentiation 40 and interleukin-4 activation of mouse B lymphocytes.

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