X-linked Recessive Disease Research Articles

Dp71 and intellectual disability in Indonesian patients with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive muscular disease marked by developmental delays due to mutations in the DMD gene, which encodes dystrophin. Brain comorbidity adds to the burden of limited mobility and significantly impacts patients' quality of life and their family. The changes of expression of dystrophin isoforms in the brain due to DMD gene mutations are thought to be related to the cognitive and neurobehavior profiles of DMD. This cross-sectional study aimed to characterize cognitive and neurodevelopmental profiles of patients with DMD and to explore underlying genotype-phenotype associations. Patients with DMD aged 5-18 years from Dr Sardjito Hospital and Universitas Gadjah Mada Academic Hospital from 2017-2022 were included. Multiplex ligation-dependent probe amplification and whole exome sequencing were used to determine mutations in the DMD genes. Cognitive function was measured by intelligence quotient testing using the Wechsler Intelligence Scale for Children and adaptive function tests with Vineland Adaptive Behavior Scales. The Autism Mental Status Exam and Abbreviated Conner's Rating Scale were used to screen for autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD), respectively. The mean total IQ score of DMD patients was lower than that of the general population (80.6 ± 22.0 vs 100 ± 15), with intellectual disability observed in 15 boys (29.4%). Of the 51 patients with DMD, the Dp71 group had the lowest cognitive performance with a total IQ score (46 ± 24.8; p = 0.003), while the Dp427 group and Dp140 group's total IQ scores were 83.0 ± 24.6 and 84.2 ± 17.5 respectively. There were no DMD patients with ASD, while 4 boys (7.8%) had comorbidity with ADHD. Boys with DMD are at higher risk of intellectual disability. The risk appears to increase with mutations at the 3' end of the gene (Dp71 disruption). Moreover, Dp71 disruption might not be associated with ADHD and ASD in patients with DMD.

P.15 Symptomatic DMD carrier as a differential diagnosis in patients presenting asymmetrical limb weakness

Duchenne/Becker muscular dystrophy (DMD) is one of the most common myopathies, characterized by an X-linked recessive disease. Asymmetrical limb weakness is rarely present in patients with muscle diseases such as ANO5-related myopathy, facioscapulohumeral muscular dystrophy, and sporadic inclusion body myositis. We report two cases of symptomatic DMD carriers presenting with asymmetrical limb weakness. A 50-year-old woman visited the department of neurology presenting with slowly progressive weakness of the limbs since childhood. A neurological examination revealed a weakness of the right arm and both legs, which were graded 4 as MRC system. Muscle MRI showed asymmetric fatty infiltration of the limbs, markedly affected by right biceps brachii, latissimus dorsi, and gastrocnemius. Immunohistochemistry (IHC) of the C-terminal region of the dystrophin gene presented several scattered stain-negative fibers. Genetic analysis revealed c.6703delG (p.Ser2235Ilefs*12, NM_004006.2) mimicking single exon 46 deletion in MLPA. A 29-year-old female presented with an elevated level of serum creatine kinase without subjective weakness. Neurologic examination showed the subtle motor weakness of the right arm, graded 4+. Muscle MRI revealed high T1 signal change on the right biceps femoris, which was not affected clinically, in addition to right biceps brachii and latissimus dorsi. IHC showed dystrophic changes and a mosaic pattern of dystrophin expression. The diagnosis was confirmed by MLPA, revealing heterozygous deletion of exon 44 in the DMD gene. Asymmetrical limb weakness can be a remark for the diagnosis of symptomatic DMD carrier. Furthermore, muscle MRI is more sensitive in detecting pathologic changes than routine neurologic examination. And single-base point mutation can mimick the exon deletion in MLPA, which needs sequencing analysis in a case of single exon deletion in DMD. Therefore, a multidisciplinary approach is mandatory for final diagnosis and a better understanding of symptomatic DMD carriers.

Generation of a homozygous TAZ knockout hESCs line by CRISPR/Cas9 system

Tafazzin (TAZ), a mitochondrial transacylase located on chromosome X, is required for the production of the mitochondrial phospholipid cardiolipin. Mutations occurring in the TAZ gene will lead to Barth syndrome, an X-linked recessive disease generally presenting as cardiomyopathy affecting males. Disease modeling strategies based on pluripotent stem cells (PSCs) provide an unprecedented and powerful platform to study Barth Syndrome. However, current studies were mostly based on male PSCs, the results and conclusions of which neglected the potential distinctions existing in disease phenotypes and mechanisms between gender. In this study, based on the H9 cell line (Female), we generated a homozygous TAZ knockout (TAZ-KO) human embryonic stem cell (hESC) line by employing CRISPR/Cas9 genome editing tools. This female TAZ-KO cell line, with normal karyotype, robust pluripotency and remarkably reduced TAZ expression, would be a useful tool for further deeply studying the pathogenesis of Barth syndrome cardiomyopathy in females.

Clinical, cytogenetic, and genomic analyses of an Ecuadorian subject with Klinefelter syndrome, recessive hemophilia A, and 1;19 chromosomal translocation: a case report

BackgroundHemophilia A is considered one of the most common severe hereditary disorders. It is an X-linked recessive disease caused by a deficiency or lack of function of the blood clotting factor VIII. Klinefelter syndrome is a genetic disorder that affects male individuals due to one or more extra X chromosomes, present in all cells or with mosaicism. The aneuploidy is due to either mitotic or meiotic chromosome non-disjunction. Chromosomal translocations are a group of genome abnormalities in which a region or regions of a chromosome break and are transferred to a nonhomologous chromosome or a new location in the same chromosome.Case presentationOur subject was born in Ecuador at 36 weeks of gestation by vaginal delivery. At 3 months old, the Factor VIII activity measure showed a 23.7% activity indicating a diagnosis of mild hemophilia A. At 1 year old, the karyotype showed an extra X chromosome, consistent with a diagnosis of Klinefelter syndrome, and a translocation between the long arms of chromosomes 1 and 19, at positions q25 and q13, respectively.ConclusionsKlinefelter syndrome and hemophilia are a rare combination. In the present case report, the subject presents both, meaning that he has inherited one X chromosome from the father and one X chromosome from the mother. Since the father has severe hemophilia A; and the subject presents a below 40% Factor VIII activity, a skewed X inactivation is suggested. Additionally, the proband presents a translocation with the karyotype 47,XXY,t(1;19)(q25;q13). No similar report with phenotypic consequences of the translocation was found. The present report highlights the importance of a correct diagnosis, based not only on the clinical manifestations of a disease but also on its genetic aspects, identifying the value of integrated diagnostics. The subject presents three different genetic alterations, Klinefelter syndrome, hemophilia A, and a 1;19 chromosomal translocation.

Rehabilitation of a 17-Year-Old Patient with X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy is an X-linked recessive disease affecting the white matter of the central nervous system along with occasional involvement of the adrenal gland due to mutation of the ABCD1 gene, which leads to accumulation of very-long-chain fatty acid (VLCFA) in the white matter of the brain and adrenal cortex. Diminished vision, speech disturbance, motor weakness, bladder–bowel involvement and adrenal insufficiency can be seen in affected individuals according to phenotype and involved area. In this case, the patient was a 17-year-old male with progressive weakness of all limbs along with the difficulty of speech and vision. Magnetic resonance imaging showed T2 hyperintensity in white matters of temporo-parieto-occipital region, splenium and body of corpus callosum, peritrigonal area, posterior limb of internal capsule and corticospinal tract location of pons and midbrain. His plasma VLCFA was elevated. Along with medical treatment, our rehabilitation team comprising a physiatrist and other supporting members provided rehabilitation management. Although different methods such as dietary modification, bone marrow transplantation and gene therapy have been tried for these types of cases globally, rehabilitation remains the backbone of the management protocol for advanced cases.

Complete Androgen Insensitivity Syndrome: A Rare Case with 47, XXY/46, XY Mosaic Karyotype and Literature Review

Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic disease caused by the absence or defects of androgen receptor (AR). Due to the insensitivity to androgen, clinically, patients often manifest as sexual development disorder.

The new challenge of "exercise + X″ therapy for Duchenne muscular dystrophy-Individualized identification of exercise tolerance and precise implementation of exercise intervention.

Duchenne muscular dystrophy (DMD) is an X-linked recessive fatal muscular disease. Gene therapy, cell therapy, and drug therapy are currently the most widely used treatments for DMD. However, many experiments on animals and humans suggested that appropriate exercise could improve the effectiveness of such precision medicine treatment, thereby improving patient’s muscle quality and function. Due to the striated muscle damage of DMD individuals, there are still many debates about whether DMD animals or patients can exercise, how to exercise, when to exercise best, and how to exercise effectively. The purpose of this review is to summarize and investigate the scientific basis and efficacy of exercise as an adjuvant therapy for DMD gene therapy, cell therapy and drug therapy, as well as to present the theoretical framework and optional strategies of “exercise + X″″ combination therapy.

Abstract P2038: Synthetic Membrane Stabilizers Reduce Serum Ck And Immune Cell Infiltrate In Neonatal Mdx Skeletal Muscle Prior To Overt Muscle Necrosis Onset In Vivo

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease caused by a mutation in the dystrophin gene resulting in a complete loss of dystrophin from the striated muscle. This leads to the disruption of the dystrophin-associated glycoprotein complex and altered mechanical and signaling functions subsequently causing membrane instability, necrosis, and progressive muscle wasting. Immune cell infiltration is a prominent feature of the DMD pathophysiology and is strongly associated with disease severity. To date, no curative treatment is available for DMD. A logical therapeutic approach for DMD is to directly target the primary defect of DMD, sarcolemma instability, and thus prevent contraction-induced membrane damage. First in class synthetic triblock copolymer, poloxamer 188 (P188), is a muscle membrane interfacing and stabilizing molecule that has been shown to protect dystrophic myocardium and skeletal muscle from acute stress induced injury in vivo . Creatine kinase (CK) is a well-established biomarker of DMD that reflects sarcolemma damage, and serum levels have been shown to dramatically increase in mdx mice, but this has not been fully characterized during the early postnatal growth period prior to overt disease onset at 3 weeks. Under standard laboratory housing conditions for adult mdx mice (6-9 month old), we found that daily administration of P188 for two weeks did not significantly change serum CK levels or Evan’s blue dye uptake by diaphragm, heart or tibialis anterior muscles. In order to evaluate P188’s ability to protect dystrophin-deficient striated muscle prior to the overt disease, serum CK levels need to be characterized during this time period to identify the earliest muscle membrane damage event in mdx striated muscle and thus the earliest time point for therapeutic intervention. Results show that mdx serum CK levels are significantly higher than control serum levels 15 days after birth and continue to increase dramatically to 20 days after birth, and then CK remains high for the lifespan. Systemic delivery of P188 to neonatal mdx mice (12 days old) prior to CK peak significantly reduced serum CK levels and blunted immune cell infiltrate as compared to saline control mdx mice. These findings support the hypothesis that early intervention with membrane stabilizers has the potential to mitigate muscle damage and blunt the inflammatory response characteristic of DMD disease pathology. More work must be done to fully understand the early pathophysiological changes associated with dystrophin deficiency in order to implement novel therapeutic strategies including membrane stabilizers to enhance the standard of care for these patients and their families.

Smad8 Is Increased in Duchenne Muscular Dystrophy and Suppresses miR-1, miR-133a, and miR-133b.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease characterized by skeletal muscle instability, progressive muscle wasting, and fibrosis. A major driver of DMD pathology stems from aberrant upregulation of transforming growth factor β (TGFβ) signaling. In this report, we investigated the major transducers of TGFβ signaling, i.e., receptor Smads (R-Smads), in DMD patient skeletal muscle and observed a 48-fold increase in Smad8 mRNA. Smad1, Smad2, Smad3, and Smad5 mRNA were only minimally increased. A similar pattern was observed in the muscle from the mdx5cv mouse. Western blot analysis showed upregulation of phosphorylated Smad1, Smad5, and Smad8 compared to total Smad indicating activation of this pathway. In parallel, we observed a profound diminishment of muscle-enriched microRNAs (myomiRs): miR-1, miR-133a, and miR-133b. The pattern of Smad8 induction and myomiR suppression was recapitulated in C2C12 muscle cells after stimulation with bone morphogenetic protein 4 (BMP4), a signaling factor that we found upregulated in DMD muscle. Silencing Smad8 in C2C12 myoblasts derepressed myomiRs and promoted myoblast differentiation; there was also a concomitant upregulation of myogenic regulatory factors (myogenin and myocyte enhancer factor 2D) and suppression of a pro-inflammatory cytokine (interleukin-6). Our data suggest that Smad8 is a negative regulator of miR-1, miR-133a, and miR-133b in muscle cells and that the BMP4-Smad8 axis is a driver of dystrophic pathology in DMD.

Variants of the DMD gene in 18 patients, clinical severity prediction, genotype-phenotype correlation, and potential therapies

Background: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive rare diseases caused by various mutations in the DMD gene which induce quantity reduction or absence of the dystrophin protein.Aims: To present variants of the DMD gene, predict clinical severity, and discuss genotype-phenotype correlation as well as potential therapies.Material and Methods: Data was collected from patients of Mother Teresa University Hospital Center, Tirana, Albania, whose diagnosis were confirmed through molecular examinations.Results: In this study, 18 male patients were enrolled. Gross mutations were detected in 11 patients, while point mutations were detected in 7 patients. The detected variants were pathogenic in 13 patients and likely pathogenic in 5 patients. The age at clinical onset was approximately 2 years old in 10 patients, 3 years old in 6 patients, 9 years old in 1 patient, and 14 years old in 1 patient. Age at the loss of ambulation was approximately 10 years in 3 patients, 11 years in 3 patients, 12 years in 2 patients, and 14 years old in 1 patient, while 9 patients are still ambulant. Signs and symptoms included muscular, skeletal, nervous, cardiovascular, and respiratory systems. Altogether, 16 patients were diagnosed with DMD and 2 patients were diagnosed with BMD.Conclusion: The genetic analysis cannot predict the course and severity of the dystrophinopathy. Genetic test results must always be evaluated in the context of clinical findings, family history, and other data, yet they are crucial for therapy customization.

Functional analysis of variants in DMD exon/intron 10 predicted to affect splicing.

Duchenne muscular dystrophy (DMD, MIM #310200) and Becker muscular dystrophy (BMD, MIM #300376) are X-linked recessive hereditary diseases caused by pathogenic variants in the DMD gene. Genetic testing of DMD identifies a certain number of variants of uncertain clinical significance (VUS) whose functional interpretations pose a challenge for gene-based diagnosis. To improve the accuracy of variant interpretation in public mutation repositories, we used computational tools to prioritize VUS and developed a cell-based minigene assay to confirm aberrant splicing. Using this procedure, we evaluated rare variants in exon and intron 10 of the DMD gene. We demonstrated that 16 variants, including both canonical and non-canonical splice sites, altered RNA splicing in variable patterns. Using the example of exon and intron 10 of the DMD gene, we demonstrated the utility of the in vitro minigene assay in the effective assessment of the spliceogenic effect for VUS identified in clinical practice and underlined the necessity of precise variant classification. This is the first systematic characterization of DMD splicing variants, besides, through our study, some undetermined variants are demonstrated to be pathogenic by altering RNA splicing of DMD.

Complete androgen insensitivity syndrome caused by a novel mutation in the androgen receptor gene and its mechanism

Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic disease characterized by disorders of sex development, commonly caused by mutations of the androgen receptor (AR) gene. Herein, we identified a novel hemizygous mutation (c.2118T > A, p. Asn706Lys) of AR resulting in complete androgen insensitivity syndrome (CAIS) in twins. This missense mutation contributed to significantly decreased mRNA transcription and protein expression. In addition, structure model analysis showed that Asn706Lys resulted in loss of hydrogen bond with Asp891 and reduced protein stability. Furthermore, the mutant AR failed to bind to ligand due to the loss of hydrogen bond with dihydrotestosterone (DHT). This disrupted the translocation of AR protein from cytoplasm to nucleus after hormone stimulation. Our findings firstly demonstrated the novel mutation of c.2118T > A in AR directly caused CAIS. This contributed to expanding the AR mutational spectrum and revealed the pathogenic mechanism of AIS, as well as facilitating precise diagnosis and genetic counseling.

BAFF rs9514828 gene polymorphism and the risk of the development of inhibitors in children with severe haemophilia A.

Haemophilia A (HA) is an x-linked recessive disease due to deficiency of coagulation factor VIII (FVIII). The development of neutralizing antibodies (inhibitors) against infused FVIII is a major concern. B cell activating factor (BAFF) has been implicated in several autoimmune diseases. We aimed to evaluate the possible association of BAFF rs9514828 gene polymorphism and the risk of the development of FVIII inhibitor in children with severe HA. This cohort study was carried out on 100 newly diagnosed boys with severe HA who were never treated before with FVIII concentrate. Assessment of serum levels of BAFF and BAFF rs9514828 genotyping at first diagnosis was performed and the patients were followed up for the completion of a total of 50 exposure days or the development of inhibitors whichever occurred first. The patients were divided as positive or negative according to the presence or absence of inhibitors. The risk allele for BAFF rs9514828 (T) was significantly more frequent in the inhibitor positive patients than the inhibitor negative patients (P=.003). In addition, CT+TT genotypes were associated with increased risk of FVIII inhibitor development. Receiver operating characteristics (ROC) analysis showed that BAFF levels could predict the development of FVIII inhibitors at a cut-off value of ≥ .92 with a sensitivity of 85.9% and a specificity of 80.2%. BAFF rs9514828 gene polymorphism could be independent risk factor and elevated BAFF levels might be useful prognostic marker for the development of FVIII inhibitor in newly diagnosed children with severe HA.

Phenotype Heterogeneity and the Association Between Visual Acuity and Outer Retinal Structure in a Cohort of Chinese X-Linked Juvenile Retinoschisis Patients

Purpose: X-linked juvenile retinoschisis (XLRS), caused by mutations in the RS1 gene, is an X-linked recessive inherited disease that typically involves both eyes in the first 2 decades of life. Recently, the phenotype heterogeneity of this condition has drawn increasing attention. We reported various phenotypes caused by RS1 gene mutations in eleven patients from ten Chinese families. Methods: Data on the medical history of the patients from ten Han families of central China were collected. Ophthalmic examinations including best-corrected visual acuity (BCVA), fundus photography, ultra-wide-angle sweep source optical coherence tomography (SS-OCT), and electroretinography (ERG) were performed. Adaptive optics (AO) images were acquired to evaluate the cone photoreceptor mosaic when applicable. Venous blood of the probands and their family members was collected, and DNA was subjected to sequencing based on next-generation sequencing with a custom-designed targeted gene panel PS400 for inherited retinal diseases. Validation was performed by Sanger sequencing and cosegregation. Pathogenicity was determined in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Ten RS1 mutations, including eight missense mutations and two terminator mutations, were identified in 10 XLRS families. c.657C > A (p.C219X) was a novel mutation in this cohort. These patients showed a variety of clinical phenotypes, including fovea schisis, bullous retinoschisis, and macular or peripheral atrophy. Fifteen eyes of eight patients exhibited macular retinoschisis, and twelve eyes of seven patients exhibited peripheral retinoschisis. In addition, three patients showed asymmetrical fundus manifestations. Of importance, three patients without macular retinoschisis were misdiagnosed until genetic testing results were obtained. AO showed a decrease in cone density and loss of regularity in the cystic schisis macular of XLRS. Furthermore, the BCVA was associated with the photoreceptor inner segment and outer segment (IS/OS) thickness. Conclusion: With complicated clinical manifestations, a considerable portion of XLRS patients may present various phenotypes. It should be noted that asymmetry in fundus appearance in both eyes could lead to misdiagnosis easily. Thus, genetic testing is crucial for making a final diagnosis in those patients who are suspected of having amblyopia, bilateral or unilateral macular atrophy, or conditions presenting an asymmetric fundus appearance. In addition, the residual cone photoreceptor structure was critical for the maintenance of useful vision.

Iduronate-2-sulfatase interactome: validation by yeast two-hybrid assay

BackgroundMucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a rare X-linked recessive disease caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), which activates intracellular accumulation of nonmetabolized glycosaminoglycans such as heparan sulfate and dermatan sulfate. This accumulation causes severe damage to several tissues, principally the central nervous system. Previously, we identified 187 IDS-protein interactions in the mouse brain. To validate a subset of these interactions, we selected and cloned the coding regions of 10 candidate genes to perform a targeted yeast two-hybrid assay. The results allowed the identification of the physical interaction of IDS with LSAMP and SYT1. Although the physiological relevance of these complexes is unknown, recent advances allow us to point out that these interactions could be involved in vesicular trafficking of IDS through the interaction with SYT1, as well as to the ability to form a transcytosis module between the cellular components of the blood-brain-barrier (BBB) through its interaction with LSAMP. These results may shed light on the role of IDS on cellular homeostasis and may also contribute to the understanding of MPS II physiopathology and the development of novel therapeutic strategies to transport recombinant IDS through the brain endothelial cells toward the brain parenchyma.

Abnormal Development of Neural Stem Cell Niche in the Dentate Gyrus of Menkes Disease.

Background and ObjectivesMenkes disease (MNK) is a rare X-linked recessive disease, caused by mutations in the copper transporting ATP7A gene that is required for copper homeostasis. MNK patients experience various clinical symptoms including neurological defects that are closely related to the prognosis of MNK patients. Neural stem cells (NSCs) in the hippocampal dentate gyrus (DG) produce new neurons throughout life, and defects in DG neurogenesis are often correlated with cognitive and behavioral problems. However, neurodevelopmental defects in the DG during postnatal period in MNK have not been understood yet.Methods and ResultsMottled-brindled (MoBr/y) mice (MNK mice) and littermate controls were used in this study. In vivo microCT imaging and immunohistochemistry results demonstrate that blood vasculatures in hippocampus are abnormally decreased in MNK mice. Furthermore, postnatal establishment of NSC population and their neurogenesis are severely compromised in the DG of MNK mice. In addition, in vitro analyses using hippocampal neurosphere culture followed by immunocytochemistry and immunoblotting suggest that neurogenesis from MNK NSCs is also significantly compromised, corresponding to defective neurogenic gene expression in MNK derived neurons.ConclusionsOur study is the first reports demonstrating that improper expansion of the postnatal NSC population followed by significant reduction of neurogenesis may contribute to neurodevelopmental symptoms in MNK. In conclusion, our results provide new insight into early neurodevelopmental defects in MNK and emphasize the needs for early diagnosis and new therapeutic strategies in the postnatal central nerve system damage of MNK patients.

Generation and characterization of an induced pluripotent stem cell line (FJMUNi001-A) from a patient with Duchenne muscular dystrophy carrying c.4518 + 512 T > A variant in the DMD gene

Duchenne muscular dystrophy (DMD) is an X-linked recessive degenerative disease characterized by progressive weakness of limbs. In this study, we generated an induced pluripotent stem cell line from a DMD patient's dermal fibroblasts with non-integrating Sendai virus. The patient carried a rare c.4518 + 512 T > A variant in the DMD gene. This iPSC line displayed normal iPSC morphology, karyotypes and pluripotency expression markers, and also can be differentiated into the three germ layers.

Dystrophic Cardiomyopathy and the Need for Cardiovascular Care

Duchenne muscular dystrophy (DMD) affects approximately 1 in 5,000 boys worldwide.1,2 This X-linked recessive disease is a result of spontaneous or inherited mutations in the dystrophin gene.3 The dystrophin gene is the longest gene in the human genome as it spans 2.5 megabases, includes 79 exons, and encodes a 427-kDa cytolinker protein.1,3 The dystrophin protein connects the interior of the cell (skeletal myocyte, cardiomyocyte, or neuron) by binding to actin via its amino terminal domain to the sarcolemma as it binds to β-dystroglycan via its carboxyterminal domain.

A human stem cell resource to decipher the biochemical and cellular basis of neurodevelopmental defects in Lowe syndrome.

ABSTRACTHuman brain development is a complex process where multiple cellular and developmental events are coordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS) is an X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1, which encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a ‘disease-in-a-dish’ model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development.This article has an associated First Person interview with the first author of the paper.

Prevalence of color vision deficiency and it’s relation with ABO blood group among medical students

Background: Normal human beings can appreciate color in all three of it’s attributes; Hue, intensity, and saturation. Human beings can perceive three primary colors, that is, red, green, and blue. Any defect in appreciation of colors is known as color vision deficiency (CVD). Complete inability to appreciate color is known as color blindness. The genes for red and green cone pigments are found in the q arm of the X chromosome. Hence, red and green CVD are inherited as X-linked recessive diseases. Blue CVD is autosomaly inherited. Blood groups are genetically inherited as well. Although it is a known fact that there is a preponderance of genetic diseases in subjects belonging to a specific blood group, no such study was available in Western Odisha as per our knowledge. This becomes more relevant as consanguineous marriages are a serious social problem in that part of Odisha. Aim and Objectives: Therefore, the study was undertaken to find out the prevalence of CVD among Medical students in Western Odisha and to find out it’s relation, if any, with ABO blood groups, as these two entities are genetically inherited. Record should be kept for future use, especially for counseling at the time of marriage and if necessary, to choose a subject for further study, where color detection does not play an important part. Materials and Methods: Prior permission was taken from the Institutional Ethics Committee to carry out this study. The study was carried out among the 1st–4th year medical students of V.S.S. Medical College and Hospital (n = 690) from August 2022 to October 2022. Ishihara test plates for color vision and agglutination method for ABO blood grouping were employed to get the prevalence of CVD and to get the percentage of subjects belonging to each blood group among those having CVD. The observations were noted carefully. Results: After careful screening, it was seen that 647 (93.76%) were normal, 42 (6.08%) had CVD, and 1 (0.14%) subject was completely color blind. All those affected were males. Distribution of blood group in CVD subjects showed 7 (16.27%) numbers belonging to blood group A, 22 (51.16%) belonging to blood group B, 1 (2.3%) belonging to blood group AB, and 12 (27.9%) belonging to blood group O. The only color blind student belonged to blood group B (2.3%). Conclusion: As medical students have to deal with colors throughout their career, the study helps the subjects to be aware of their condition early in their professional life. It also tried to find out the percentage distribution into ABO blood groups. A larger population should be included to get more accurate results.