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Hematology Reports Jun 2024Hypopigmentation disorders pose significant diagnostic challenges in dermatology, sometimes reflecting underlying hematological conditions. This review explores the... (Review)
Review
Hypopigmentation disorders pose significant diagnostic challenges in dermatology, sometimes reflecting underlying hematological conditions. This review explores the clinical presentations related to hypopigmentation in hematological disorders, focusing on vitiligo, morphea, and syndromic albinism. Vitiligo, an autoimmune disorder targeting melanocytes, involves interactions between genetic polymorphisms and immune responses, particularly regarding CD8+ T cells and IFN-γ. Drug-induced vitiligo, notably by immune checkpoint inhibitors and small-molecule targeted anticancer therapies, underscores the importance of immune dysregulation. Morphea, an inflammatory skin disorder, may signal hematological involvement, as seen in deep morphea and post-radiotherapy lesions. Syndromic albinism, linked to various genetic mutations affecting melanin production, often presents with hematologic abnormalities. Treatment approaches focus on targeting the immune pathways specific to the condition, and when that is not possible, managing symptoms. Understanding these dermatological manifestations is crucial for the timely diagnosis and management of hematological disorders.
PubMed: 38921184
DOI: 10.3390/hematolrep16020036 -
Hematology Reports May 2024Viral infections, including those caused by COVID-19, can produce striking morphologic changes in peripheral blood. Distinguishing between reactive changes and abnormal...
Viral infections, including those caused by COVID-19, can produce striking morphologic changes in peripheral blood. Distinguishing between reactive changes and abnormal morphology of monocytes remains particularly difficult, with low consensus rates reported amongst hematopathologists. Here, we report a patient who developed transient monocytosis of 11.06 × 10/L with 32% promonocytes and 1% blasts during hospitalization that was secondary to severe COVID-19 infection. Three days later, the clinical status of the patient improved and the WBC had decreased to 8.47 × 10/L with 2.2 × 10/L monocytes. Flow cytometry studies did not reveal immunophenotypic findings specific for an overt malignant population. At no time during admission did the patient develop cytopenia(s), and she was discharged upon clinical improvement. However, the peripheral blood sample containing promonocytes was sent for molecular testing with an extended next-generation sequencing myeloid panel and was positive for pathogenic Type A and R882H mutations. Subsequently, despite an essentially normal complete blood count, the patient underwent a bone marrow assessment that showed acute myeloid leukemia with 77% promonocytes. This case emphasizes the critical importance of a full work up to exclude acute leukemia when classical promonocyte morphology is encountered in the peripheral blood. Promonocytes are not a part of the reactive changes associated with COVID-19 and remain specific to myeloid neoplasia.
PubMed: 38921181
DOI: 10.3390/hematolrep16020033 -
Cells Jun 2024gene loss-of-function mutation leads to Primary Ciliary Dyskinesia (PCD), a disease caused by motile cilia dysfunction. Previously, we demonstrated that knockout of the...
gene loss-of-function mutation leads to Primary Ciliary Dyskinesia (PCD), a disease caused by motile cilia dysfunction. Previously, we demonstrated that knockout of the gene in mice replicates several features of PCD, such as hydrocephalus, defects in left-right body symmetry, and male infertility, with a complete absence of sperm in the reproductive tract. The majority of knockout animals die before sexual maturation due to severe hydrocephalus and failure to thrive, which precludes fertility studies. Here, we performed the expression analysis of the gene during gonad development and in adult testes. We showed that starts its expression during the first wave of spermatogenesis, specifically at the meiotic stage, and that its expression is restricted to the germ cells in the adult testes, suggesting that plays a role in spermatozoa formation. Subsequently, we conditionally deleted the gene in adult males and demonstrated that even partial ablation of the gene leads to asthenoteratozoospermia with multiple morphological abnormalities of sperm flagella (MMAF) in mice. The analysis of the seminiferous tubules in -deficient mice revealed defects in spermatogenesis with accumulation of seminiferous tubules at the spermiogenesis and spermiation phases. Furthermore, analysis of fertility in heterozygous knockout mice revealed a reduction in sperm count and motility as well as abnormal sperm morphology. Additionally, males exhibited a shorter fertile lifespan. Overall, these results suggest the important role of and gene dosage in male fertility. These findings may have an impact on the genetic and fertility counseling practice of PCD patients carrying loss-of-function mutations.
Topics: Animals; Male; Spermatogenesis; Fertility; Mice; Spermatozoa; Mice, Knockout; Testis; Infertility, Male; Mice, Inbred C57BL
PubMed: 38920681
DOI: 10.3390/cells13121053 -
Journal of Biosciences 2024Cystic fibrosis (CF) is a life-threatening monogenic disease affecting thousands of people worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) is an... (Review)
Review
Cystic fibrosis (CF) is a life-threatening monogenic disease affecting thousands of people worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that facilitates transportation of water and salts across epithelial cell membranes through the conductance of Cl and other anions. A dysfunctional CFTR due to abnormalities in the gene causes CF, which is believed to be a rare disease in India mainly due to mis/underdiagnosis. Although numerous diagnostic methods and treatment options are available for CF globally, most of these are unaffordable for developing countries like India. Currently, CF symptoms are managed with mucolytics, antibiotics, anti-inflammatory drugs, and various CFTR modulators based on the type of defect. While a definitive cure for CF remains elusive, advancements in stem cell and gene therapies hold promise for permanent cure in the near future. In this review, we discuss the prevalence of CF cases in India, affordable diagnostic methods, and treatment options amenable for developing countries. We further emphasize the scope for the universal newborn screening programme.
Topics: Cystic Fibrosis; Humans; India; Cystic Fibrosis Transmembrane Conductance Regulator; Developing Countries; Genetic Therapy; Neonatal Screening; Infant, Newborn; Mutation
PubMed: 38920104
DOI: No ID Found -
BMC Nephrology Jun 2024Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited cystic disease characterized by bilateral renal cyst formation and congenital liver fibrosis....
BACKGROUND
Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited cystic disease characterized by bilateral renal cyst formation and congenital liver fibrosis. Cardiovascular disorders such as noncompaction of ventricular myocardium (NVM) have not been reported with ARPKD.
CASE PRESENTATION
A 5-month-old girl was examined after presenting with a fever and turbid urine for one day and was diagnosed as urinary tract infection. Urinary ultrasound showed multiple round, small cysts varying in size in both kidneys. Genetic testing revealed two heterozygous mutations and one exon deletion in the polycystic kidney and hepatic disease 1 gene, indicating a diagnosis of ARPKD. During hospitalization, she was found to have chronic heart failure after respiratory tract infection, with an ejection fraction of 29% and fraction shortening of 13%. When the patient was 15 months old, it was found that she had prominent trabeculations and deep intertrabecular recesses with the appearance of blood flow from the ventricular cavity into the intertrabecular recesses by echocardiography. The noncompaction myocardium was 0.716 cm and compaction myocardium was 0.221 cm (N/C = 3.27), indicating a diagnosis of NVM. Liver and kidney function remained normal during four-year follow-up.
CONCLUSIONS
This is the first report of NVM in a patient with ARPKD. It is unsure if the coexistence of NVM and ARPKD is a coincidence or they are different manifestations of ciliary dysfunction in the heart and kidneys.
Topics: Humans; Female; Polycystic Kidney, Autosomal Recessive; Infant; Isolated Noncompaction of the Ventricular Myocardium; Ciliopathies
PubMed: 38918687
DOI: 10.1186/s12882-024-03642-7 -
Frontiers in Genetics 2024Differences/disorders of sex development (DSDs) in individuals with a 46, XY karyotype are a group of congenital disorders that manifest as male gonadal hypoplasia or... (Review)
Review
Differences/disorders of sex development (DSDs) in individuals with a 46, XY karyotype are a group of congenital disorders that manifest as male gonadal hypoplasia or abnormalities of the external genitalia. Approximately 50% of patients with 46, XY DSDs cannot obtain a molecular diagnosis. The aims of this paper were to review the most common causative genes and rare genes in patients with 46, XY DSDs, analyze global molecular diagnostic cohorts for the prevalence and geographic distribution of causative genes, and identify the factors affecting cohort detection results. Although the spectrum of genetic variants varies across regions and the severity of the clinical phenotype varies across patients, next-generation sequencing (NGS), the most commonly used detection method, can still reveal genetic variants and aid in diagnosis. A comparison of the detection rates of various sequencing modalities revealed that whole-exome sequencing (WES) facilitates a greater rate of molecular diagnosis of the disease than panel sequencing. Whole-genome sequencing (WGS), third-generation sequencing, and algorithm advancements will contribute to the improvement of detection efficiency. The most commonly mutated genes associated with androgen synthesis and action are , , and , and the most commonly mutated genes involved in gonadal formation are and Detection results are affected by differences in enrollment criteria and sequencing technologies.
PubMed: 38915825
DOI: 10.3389/fgene.2024.1387598 -
Frontiers in Neurology 2024Huntington's disease (HD) is a debilitating neurodegenerative condition characterized by motor, cognitive and psychiatric abnormalities. Immune dysregulation,...
Huntington's disease (HD) is a debilitating neurodegenerative condition characterized by motor, cognitive and psychiatric abnormalities. Immune dysregulation, prominently featuring increased immune activity, plays a significant role in HD pathogenesis. In addition to the central nervous system (CNS), systemic innate immune activation and inflammation are observed in HD patients, exacerbating the effects of the Huntingtin (HTT) gene mutation. Recent attention to sex differences in HD symptom severity underscores the need to consider gender as a biological variable in neurodegenerative disease research. Understanding sex-specific immune responses holds promise for elucidating HD pathophysiology and informing targeted treatment strategies to mitigate cognitive and functional decline. This perspective will highlight the importance of investigating gender influence in HD, particularly focusing on sex-specific immune responses predisposing individuals to disease.
PubMed: 38915800
DOI: 10.3389/fneur.2024.1384480 -
BioRxiv : the Preprint Server For... Jun 2024ECHS1 Deficiency (ECHS1D) is a rare and devastating pediatric disease that currently has no defined treatments. This disorder results from missense loss-of-function...
ECHS1 Deficiency (ECHS1D) is a rare and devastating pediatric disease that currently has no defined treatments. This disorder results from missense loss-of-function mutations in the gene that result in severe developmental delays, encephalopathy, hypotonia, and early death. ECHS1 enzymatic activity is necessary for the beta-oxidation of fatty acids and the oxidation of branched-chain amino acids within the inner mitochondrial matrix. The pathogenesis of disease remains unknown, however it is hypothesized that disease is driven by an accumulation of toxic metabolites from impaired valine oxidation. To expand our knowledge on disease mechanisms, a novel mouse model of ECHS1D was generated that possesses a disease-associated knock-in (KI) allele and a knock-out (KO) allele. To investigate the behavioral phenotype, a battery of testing was performed at multiple time points, which included assessments of learning, motor function, endurance, sensory responses, and anxiety. Neurological abnormalities were assessed using wireless telemetry EEG recordings, pentylenetetrazol (PTZ) seizure induction, and immunohistochemistry. Metabolic perturbations were measured within the liver, serum, and brain using mass spectrometry and magnetic resonance spectroscopy. To test disease mechanisms, mice were subjected to disease pathway stressors and then survival, body weight gain, and epilepsy were assessed. Mice containing KI/KI or KI/KO alleles were viable with normal development and survival, and the presence of KI and KO alleles resulted in a significant reduction in ECHS1 protein. ECHS1D mice displayed reduced exercise capacity and pain sensation. EEG analysis revealed increased slow wave power that was associated with perturbations in sleep. ECHS1D mice had significantly increased epileptiform EEG discharges, and were sensitive to seizure induction, which resulted in death of 60% of ECHS1D mice. Under basal conditions, brain structure was grossly normal, although histological analysis revealed increased microglial activation in aged ECHS1D mice. Increased dietary valine only affected ECHS1D mice, which significantly exacerbated seizure susceptibility and resulted in death. Lastly, acute inflammatory challenge drove regression and early lethality in ECHS1D mice. In conclusion, we developed a novel model of ECHS1D that may be used to further knowledge on disease mechanisms and to develop therapeutics. Our data suggests altered metabolic signaling and inflammation may contribute to epilepsy in ECHS1D, and these alterations may be attributed to impaired valine metabolism.
PubMed: 38915588
DOI: 10.1101/2024.06.13.598697 -
Molecular Biology Research... 2024Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the abnormal and rapid growth of cells. The mutation of the Fms-like...
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the abnormal and rapid growth of cells. The mutation of the Fms-like tyrosine kinase 3 ligand gene (-ITD) represents an important factor in the prognosis of AML. The objective of this study was to determine for the first time the prevalence of -ITD mutation in west Algerian AML patients. A total of 160 AML patients were genotyped for -ITD mutation by using polymerase chain reaction. -ITD mutation was detected in 13% of patients. Mutation rates show no significant difference in the distribution of sex and age. A positive association was found between this mutation and a higher leukocyte and blast cells counts. We also found that the M3 and M5 subtype were the commonest in the mutated group. This preliminary study provides first-time prevalence estimates for -ITD mutation in acute myeloid leukemia patients from the West region of Algeria.
PubMed: 38915455
DOI: 10.22099/mbrc.2024.49437.1955 -
Italian Journal of Pediatrics Jun 2024Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by imperforate anus, dysplastic ears, thumb malformations, and other abnormalities. Previous...
BACKGROUND
Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by imperforate anus, dysplastic ears, thumb malformations, and other abnormalities. Previous studies have revealed that mutations in the SALL1 gene can disrupt normal development, resulting in the characteristic features of Townes-Brocks syndrome. Spalt-like transcription factors (SALLs) are highly conserved proteins that play important roles in various cellular processes, including embryonic development, cell differentiation, and cell survival. Over 400 different variants or mutations have been reported in the SALL1 gene in individuals with TBS. Most of these variants lead to the formation of premature termination codons (PTCs), also known as nonsense mutations. The majority of these PTCs occur in a specific region of the SALL1 gene called the "hotspot region", which is particularly susceptible to mutation.
METHODS
In this study, we conducted whole-exome sequencing on a three-generation Chinese family with anorectal malformations.
RESULTS
We identified a novel heterozygous mutation (chr16:51175376:c.757 C > T p.Gln253*) in the SALL1 gene. Molecular analysis revealed a heterozygous C to T transition at nucleotide position 757 in exon 2 of the SALL1 (NM_002968) gene. This mutation is predicted to result in the substitution of the Gln253 codon with a premature stop codon (p.Gln253*). The glutamine-rich domain forms a long alpha helix, enabling the mutant protein to interact with the wild-type SALL1 protein. This interaction may result in steric hindrance effects on the wild-type SALL1 protein.
CONCLUSIONS
Our findings have expanded the mutation database of the SALL1 gene, which is significant for genetic counseling and clinical surveillance in the affected family. Furthermore, our study enhances the understanding of Townes-Brocks syndrome and has the potential to improve its diagnosis and treatment.
Topics: Humans; Transcription Factors; Abnormalities, Multiple; Anus, Imperforate; Female; Male; Pedigree; China; Mutation; Rare Diseases; Anorectal Malformations; Asian People; East Asian People; Hearing Loss, Sensorineural; Thumb
PubMed: 38915054
DOI: 10.1186/s13052-024-01691-0