Autosomal Recessive Pattern Of Inheritance Research Articles

A Case of Rafiq Syndrome (MAN1B1-CDG) in a Palestinian Child, With Brief Literature Review of 44 Cases.

Rafiq syndrome, MAN1B1-CDG, was described in 2010 and associated with genetic mutation in MAN1B1 gene in 2011. The disorder follows an autosomal recessive pattern of inheritance and typically presents with specific facial dysmorphism, intellectual disability, developmental delay, obesity, and hypotonia. The syndrome belongs to a group of metabolic disorders called Congenital Glycosylation Disorders (CGD). In this study, we discuss a 5-year-old male from Palestine who presented with developmental delay, hypotonia, characteristic facial dysmorphisms, impulsive behaviors, inability to speak, cryptorchidism, and other manifestations. This constellation of manifestations raised suspicion of a genetic disorder, prompting whole exome sequencing (WES), which revealed the presence of a homozygous likely pathogenic variant in the MAN1B1 gene (c.1976T>G)(p.Phe659Cys). We also reviewed all previously documented cases and compared the clinical features among them. After reviewing the family pedigree and its suspected cases, we found that the 2 most frequent features among them are intellectual disability and facial dysmorphism, whereas the least frequent one is truncal obesity. We discussed the importance of providing genetic counseling to parents of children with this and other rare, autosomal recessive disorders to prevent new cases from appearing.

Behavioral and Electrophysiological Assessment of Central Auditory Processing in Individuals with Sickle Cell Disease.

Sickle cell anemia has a genetic origin characterized by an autosomal recessive inheritance pattern. The nervous system may be subject to vaso-occlusion and, consequently, affect the proper functioning of the central portion of hearing. To assess central auditory skills and analyze short- and long-latency auditory evoked potentials in children with sickle cell disease. Cross-sectional study. All children had normal hearing thresholds, and their central auditory processing underwent behavioral assessment with a battery of tests involving dichotic and monotic listening, binaural interaction, and temporal processing. The electrophysiological assessment used short- and long-latency auditory evoked potentials. Descriptive statistics were performed. Of the 28 subjects evaluated (mean age of 9.46years), 18 were females and 10 were males. Central auditory processing disorder was identified in 85.7% of the children. The auditory skills of figure-ground for verbal sounds, binaural interaction, and complex temporal ordering were the most affected. An increase in the absolute latencies of Waves III and V was observed in the short-latency potential. Individuals with sickle cell disease have central auditory processing disorder, identified primarily by behavioral assessment.

Recessive but damaging alleles of muscle-specific ribosomal protein gene RPL3L drive neonatal dilated cardiomyopathy.

The heart employs a specialized ribosome in its muscle cells to translate genetic information into proteins, a fundamental adaptation with an elusive physiological role. Its significance is underscored by the discovery of neonatal patients suffering from often fatal heart failure caused by rare compound heterozygous variants in RPL3L, a muscle-specific ribosomal protein that replaces the ubiquitous RPL3 in cardiac ribosomes. RPL3L -linked heart failure represents the only known human disease arising from mutations in tissue-specific ribosomes, yet the underlying pathogenetic mechanisms remain poorly understood despite an increasing number of reported cases. While the autosomal recessive inheritance pattern suggests a loss-of-function mechanism, Rpl3l -knockout mice display only mild phenotypes, attributed to up-regulation of the ubiquitous Rpl3. Interestingly, living human knockouts of RPL3L have been identified. Here, we report two new cases of RPL3L -linked severe neonatal heart failure and uncover an unusual pathogenetic mechanism through integrated analyses of population genetic data, patient cardiac tissue, and isogenic cells expressing RPL3L variants. Our findings demonstrate that patient hearts lack sufficient RPL3 compensation. Moreover, contrary to a simple loss-of-function mechanism often associated with autosomal recessive diseases, RPL3L -linked disease is driven by a combination of gain-of-toxicity and loss-of-function. Most patients carry a recurrent toxic missense variant alongside a non-recurrent loss-of-function variant. The non-recurrent variants trigger partial compensation of RPL3 similar to Rpl3l -knockout mice. In contrast, the recurrent missense variants exhibit increased affinity for the RPL3/RPL3L chaperone GRWD1 and 60S biogenesis factors, sequester 28S rRNA in the nucleus, disrupt ribosome biogenesis, and trigger severe cellular toxicity that extends beyond the loss of ribosomes. These findings elucidate the pathogenetic mechanisms underlying muscle-specific ribosome dysfunction in neonatal heart failure, providing critical insights for genetic screening and therapeutic development. Our findings also suggest that gain-of-toxicity mechanisms may be more widespread in autosomal recessive diseases, especially for those involving genes with paralogs.

Mechano-electrical transduction components TMC1-CIB2 undergo a Ca2+-induced conformational change linked to hearing loss.

TMC1, a unique causative gene associated with deafness, exhibits variants with autosomal dominant and recessive inheritance patterns. TMC1 codes for the transmembrane channel-like protein 1 (TMC1), a key component of the mechano-electrical transduction (MET) machinery for hearing. However, the molecular mechanism of Ca2+ regulation in MET remains unclear. Calcium and integrin-binding protein 2 (CIB2), another MET component associated with deafness, can bind with Ca2+. Our study shows that TMC1-CIB2 complex undergoes a Ca2+-induced conformational change. We identified a vertebrate-specific binding site on TMC1 that interacts with apo CIB2, linked with hearing loss. Using an exvivo mouse organotypic cochlea model, we demonstrated that disruption of the calcium-binding site of CIB2 perturbs the MET channel conductivity. After systematically analyzing the hearing loss variants, we observed dominant mutations of TMC1 cluster around the putative ion pore or at the binding interfaces with CIB2. These findings elucidate the molecular mechanisms underlying TMC1-linked hearing loss.

SPOUT1 variants associated with autosomal-recessive developmental and epileptic encephalopathy

BackgroundDevelopmental and epileptic encephalopathy (DEE) is a group of neurodevelopmental disorders characterized by early-onset seizures predominantly attributed to genetic causes. Nevertheless, numerous patients remain without identification of a genetic cause.MethodsWe present four unrelated Chinese patients with SPOUT1 compound heterozygous variants, all of whom were diagnosed with DEE. We also investigated functions of SPOUT1 using the spout1 knockout zebrafish model.ResultsThe four unrelated DEE patients with SPOUT1 compound heterozygous variants were all males. Their onset age of seizure ranged from 3 months to 6 months (median age 5 months). All patients had epileptic spasms, and were diagnosed with infantile epileptic spasms syndrome (IESS). Three patients had microcephaly during infancy. Brain MRI in three patients showed white matter hypomyelination and bilaterally widened frontotemporal subarachnoid space. At the last follow-up, two patients exhibited drug-resistant epilepsy, one achieved seizure freedom following vigabatrin treatment, and one died at the age of 4 years and 5 months from probable sudden unexpected death in epilepsy. Seven different SPOUT1 variants were identified in the four patients, including six missense variants and one deletion variant. AlphaFold2 prediction indicated that all variants alternated the number or the length of bonds between animo acids in protein SPOUT1. Neurophysiological results from spout1 knockout zebrafish revealed the presence of epileptiform signals in 9 out of 63 spout1 knockout zebrafishes (P = 0.009). Transcriptome sequencing revealed 21 differentially expressed genes between spout1 knockout and control groups, including 13 up-regulated and 8 down-regulated genes. Two axonal transport-related genes, kif3a and ap3d1, were most prominently involved in enriched Gene Ontology (GO) terms.ConclusionsThis study identified SPOUT1 as a novel candidate gene of DEE, which follows the autosomal-recessive inheritance pattern. IESS is the most common epilepsy syndrome. Downregulation of axonal transport-related genes, KIF3A and AP3D1, may play a crucial role in the pathogenesis of DEE.

Зміни фізичного розвитку в дітей при муковісцидозі як універсальний механізм пристосування організму

Cystic fibrosis (CF) is the most common monogenic disorder with an autosomal recessive inheritance pattern. The disease leads to damage to the respiratory system, pancreas, intestines, gallbladder and liver. In Ukraine, about 300 children are born with CF each year. As of 2024, there are 16 children with CF living in the Ternopil region. Aim - to analyze the parameters of physical development in children with CF to understand the processes of adaptation and maladaptation of the child's body under conditions of chronic hypoxia, which causes dehydration. Materials and methods. The study was conducted by analyzing the records of hospitalized 15 patients who were receiving inpatient treatment at the Ternopil Regional Clinical Children's Hospital and conducting a literature search of scientific publications from sources such as PubMed, ResearchGate, and Science. Results. Impairment of physical development, growth and weight gain is one of the most common problems faced by children with CF. The comparison of body mass-to-height ratio (WFLz) and body mass index (BMIz) indicators was carried out as an as assessments of physical development and possible malnutrition in children with CF. Problems with gaining and maintaining weight indicate that the digestive system is not absorbing the nutrients necessary for the child's growth, disrupting adaptation processes. Conclusions. As a result of the study, no significant impairment of the physical development of children with CF was found, in 10 (66.7%) patients physiological norms were established based on the ratio of body weight to height. As a result of the comparison of BMI indicators, 13 (86.7%) patients were within the physiological deviation range. No conflict of interests was declared by the authors.

Differential expression of keratin and keratin associated proteins are linked with hair loss condition in spontaneously mutated inbred mice

Hair loss condition is heritable and is influenced by multifactorial inheritance. In the present study, spontaneously mutated mice showed hair loss phenotype with defect in the first cycle of hair follicle formation leading to cyclic alopecia. These mutant mice follow autosomal recessive inheritance pattern. The transcriptomic profile and differential gene expression analysis of skin tissues by RNA-sequencing at different stages of hair cycle formation was performed. The genes with significant differential genes expression levels in each stage of hair cycle formation were identified and most of these genes were shown to be associated with keratinization process and hair follicle formation. Transcriptome profiling followed by QPCR validation revealed that mRNA levels of Krt16, Alox15, Fetub (upregulated) and Msx2 (downregulated) were significantly differentially expressed in mutant skin tissues during late anagen and catagen stages. Krt6b mRNA and protein levels were significantly higher in the mutant mice during all stages of first hair cycle formation. The present study provides basis for understanding the differential gene expression of hair-related genes, including keratinization-associated proteins and its relevance. These mutant mice can serve as a model for studying hair loss condition that can be further used in the identification, evaluation and treatment strategies for alopecia condition.

Bleeding Phenotype of Glanzmann Thrombasthenia (GT) and Treatment Outcomes in Over One Hundred Patients: A Two-Center Experience in North Pakistan.

Glanzmann thrombasthenia (GT) is a rare disease with an autosomal recessive inheritance pattern. This disorder is not so uncommonly encountered in routine clinical practice and laboratory settings in Pakistan let alone in the rest of the world. To describe the bleeding phenotype of GT and treatment outcomes in over one hundred patients in north Pakistan. This descriptive, cross-sectional, retrospective study was conducted on patients from 2011 to 2023 using a convenience sampling technique.A total of 103 patients of all ages and both genders diagnosed as having inherited GT were included in the study. The median age of the study population was 1.1 years, with an interquartile range (IQR) of 0.8-2. Out of the total, 55 (53%) patients were males and 48 (47%) patients were females. Ninety-eight percent of patients were diagnosed using light transmission aggregometry, and only two (2%) patients were diagnosedby immunophenotyping. Due to the high incidence of interfamily marriages, 86 (84%) patients were born to consanguineous marriages. Thirty-nine (38%) patients had an episode of major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria. Epistaxis in 73 (71%) patients, skin bruising in 63 (61%), and gum bleeding in 57 (55%) were the most common bleeding symptoms. Thirty-two (31%) required the use of r-VIIa for major bleedingand five (5%) patients underwent fully matched allogeneic HSCT (hematopoietic stem cell transplant). Graft versus host disease-free relapse-free survival (GRFS) was 80%. GT is still an underrecognized and underdiagnosed disorder, particularly in resource-limited settings where the estimated incidence seems to be much higher than reported.

Abstract 4136394: Elucidation of a novel genetic substrate responsible for genetically elusive ring-like arrhythmogenic cardiomyopathy

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic heart disease characterized by fibrofatty replacement of ventricular myocardium. Arrhythmogenic left ventricular (LV) cardiomyopathy (ALVC) is a phenotypic variant of ACM predominantly involving the LV. Mutations in genes encoding for desmosome proteins and filamin C have been implicated in ALVC, especially in the setting of a ring-like late gadolinium enhancement (LGE) imaging pattern. Objective: To identify the underlying genetic substrate responsible for genetically elusive ring-like ALVC in a patient with seemingly sporadic/recessive disease. Methods: A 38-year-old male was referred for genetic investigation to determine the underlying genetic substrate responsible for his ALVC phenotype. The patient fulfilled both electrocardiographic (low voltage in the limb leads and anterolateral T-wave inversions) and imaging (>1 segment of subepicardial LGE) criteria for ALVC. Additionally, the patient experienced unexplained episodes of tachycardia, shakiness, sweating, and nausea prompting concern for an underlying neuromuscular disease. Genome sequencing (GS) was performed on DNA isolated from the affected patient and both of his unaffected parents. Variants were filtered assuming either a sporadic de novo occurrence or an autosomal recessive inheritance pattern. Results: GS identified compound heterozygous GNPTAB variants in the affected patient. A previously reported maternally derived p.Leu257Leu (c.771G>A) variant involving the last nucleotide of exon 7 of the GNPTAB gene and a novel paternally inherited Lys834fs*5 frame-shift variant were identified. The p.Leu257Leu variant has been reported to cause aberrant splicing and exon skipping of the GNPTAB mRNA transcript. Pathogenic variants in the GNPTAB encoded N-acetylglucosamine-1 (GlcNAc)-phosphotransferase subunits alpha/beta cause mucolipidosis type III, a rare recessive lysosomal storage disease characterized by coarse facial features, developmental delay, short stature, skeletal deformities, and cardiac involvement including valvular thickening and cardiomyopathy. Conclusions: Here, using a genome sequencing trio analysis we identified a compound heterozygous GNPTAB pathogenic variants as the underlying genetic substrate in a patient with ring-like ALVC and concomitant neuromuscular disease manifestation. Genome sequencing may identify the genetic etiology responsible for an otherwise undifferentiated diagnosis of cardiomyopathy.

The cumulative effect of compound heterozygous variants in TRPV3 caused Olmsted syndrome

BackgroundOlmsted syndrome (OS) is a rare genodermatosis predominantly inherited in an autosomal dominant manner, typically arising from gain-of-function (GOF) variants in the transient receptor potential channel vanilloid 3 (TRPV3) gene. ObjectiveThis study aims to investigate potential mechanisms underlying OS in two cases presenting with an autosomal recessive inheritance pattern. MethodsNext-generation sequencing panel was employed to identify TRPV3 variants. TRPV3 plasmids carrying specific point variations were generated and transiently transfected into HEK293T cells. Electrophysiological patch-clamp techniques were utilized to record voltage-activated and ligand-activated currents. Celltiter-Glo luminescent assay was employed to analyze the cell viabilities. ResultsCompound heterozygous variants, c.1563 G>C (p.W521C) and c.1376 C>T (p.S459L), as well as c.1773 G>C (p.L591F) and c.2186 G>A (p.R729Q), were identified in the two OS patients respectively. Electrophysiological analysis of ligand-induced activation of TRPV3 variants demonstrated the closest correlation with clinical manifestations. All four variants displayed GOF channel activity characterized by increased sensitivity. Notably, W521C and L591F exhibited both heightened sensitivity and lower EC50 values for the TRPV3 agonist. Co-transfection with wild-type TRPV3 plasmids significantly rescued these effects. Cells co-transfected with the corresponding compound heterozygous variants exhibited intermediate electrophysiological characteristics. ConclusionsIn this study, we present two cases of OS by autosomal-recessive inheritance of TPRV3 variants. This study presents a notable observation of compound heterozygous GOF variants in TRPV3, highlighting their cumulative impact on clinical manifestations. Additionally, we advocate for the use of ligand-dependent ion channel activity assays to assess the pathogenicity of TRPV3 variants in OS.

New and de novo Biallelic Variant Associated with Owren’s Disease: Precision Medicine in Coagulation Disorders

Introduction: Coagulation factor V deficiency, also called Owren’s disease or parahemophilia [1], is a genetic disease with an autosomal recessive inheritance pattern that causes moderate to severe bleeding [2]. It can be classified into type I when the deficiency is quantitative and type II when the deficiency is qualitative [3]. Currently, it is associated with variants in the F5 gene. According to recent database searches, 450 clinically significant variants and approximately 3942 variants related to the F5 gene have been identified [2].

Expanding the genetic spectrum of hereditary motor sensory neuropathies in Pakistan

BackgroundHereditary motor and sensory neuropathy (HMSN) refers to a group of inherited progressive peripheral neuropathies characterized by reduced nerve conduction velocity with chronic segmental demyelination and/or axonal degeneration. HMSN is highly clinically and genetically heterogeneous with multiple inheritance patterns and phenotypic overlap with other inherited neuropathies and neurodegenerative diseases. Due to this high complexity and genetic heterogeneity, this study aimed to elucidate the genetic causes of HMSN in Pakistani families using Whole Exome Sequencing (WES) for variant identification and Sanger sequencing for validation and segregation analysis, facilitating accurate clinical diagnosis.MethodsFamilies from Khyber Pakhtunkhwa with at least two members showing HMSN symptoms, who had not previously undergone genetic analysis, were included. Referrals for genetic investigations were based on clinical features suggestive of HMSN by local neurologists. WES was performed on affected individuals from each family, with Sanger sequencing used to validate and analyze the segregation of identified variants among family members. Clinical data including age of onset were assessed for variability among affected individuals, and the success rate of genetic diagnosis was compared with existing literature using proportional differences and Cohen’s h.ResultsWES identified homozygous pathogenic variants in GDAP1 (c.310 + 4 A > G, p.?), SETX (c.5948_5949del, p.(Asn1984Profs*30), IGHMBP2 (c.1591 C > A, p.(Pro531Thr) and NARS1 (c.1633 C > T, p.(Arg545Cys) as causative for HMSN in five out of nine families, consistent with an autosomal recessive inheritance pattern. Additionally, in families with HMSN, a SETX variant was found to cause cerebellar ataxia, while a NARS1 variant was linked to intellectual disability. Based on American College of Medical Genetics and Genomics criteria, the GDAP1 variant is classified as a variant of uncertain significance, while variants in SETX and IGHMBP2 are classified as pathogenic, and the NARS1 variant is classified as likely pathogenic. The age of onset ranged from 1 to 15 years (Mean = 5.13, SD = 3.61), and a genetic diagnosis was achieved in 55.56% of families with HMSN, with small effect sizes compared to previous studies.ConclusionsThis study expands the molecular genetic spectrum of HMSN and HMSN plus type neuropathies in Pakistan and facilitates accurate diagnosis, genetic counseling, and clinical management for affected families.

Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia.

Variation in the non-coding genome represents an understudied mechanism of disease and it remains challenging to predict if single nucleotide variants, small insertions and deletions, or structural variants in non-coding genomic regions will be detrimental. Our approach using complementary RNA-seq and targeted long-read DNA sequencing can prioritize identification of non-coding variants that lead to disease via alteration of gene splicing or expression. We have identified a patient with primary ciliary dyskinesia with a pathogenic coding variant on one allele of the SPAG1 gene, while the second allele appears normal by whole exome sequencing despite an autosomal recessive inheritance pattern. RNA sequencing revealed reduced SPAG1 transcript levels and exclusive allele specific expression of the known pathogenic allele, suggesting the presence of a non-coding variant on the second allele that impacts transcription. Targeted long-read DNA sequencing identified a heterozygous 3 kilobase deletion of the 5' untranslated region of SPAG1, overlapping the promoter and first non-coding exon. This non-coding deletion was missed by whole exome sequencing and gene-specific deletion/duplication analysis, highlighting the importance of investigating the non-coding genome in patients with "missing" disease-causing variation. This paradigm demonstrates the utility of both RNA and long-read DNA sequencing in identifying pathogenic non-coding variants in patients with unexplained genetic disease.

The unlikely combination: Anderson-Fabry disease and congenital dyserythropoietic anemia type II in a pediatric patient.

Anderson-Fabry disease, a rare X-linked lysosomal disorder, and congenital dyserythropoietic anemia (CDA) Type II, an autosomal recessive condition, both have distinct inheritance patterns. Their co-occurrence is extremely rare, never been reported before. Therefore, screening is crucial for early management, and families should seek genetic counseling for children showing unusual presentations. Anderson-Fabry disease (AFD) is a rare condition, characterized by a lysosomal storage disorder affecting lipid storage. It manifests in two forms: classic (early-onset) and nonclassic (late-onset). Conversely, congenital dyserythropoietic anemia (CDA) is a rare blood disorder caused by ineffective erythropoiesis, which results in the production of abnormal erythroblasts during the maturation of red blood cells, with CDA type II being the most frequent type. Both disorders have well-understood pathophysiologies, yet they are genetically distinct. AFD is inherited in an X-linked manner, whereas CDA type II follows an autosomal recessive pattern of inheritance. Although both AFD and CDA type II have been reported separately in the literature. The co-existence for both AFD and CDA type II has not been reported. We describe a 10-year-old boy, with both which is believed to be the first documented case.

DNAH17 deficiency causes disruption in the assembly and docking of sperm flagellar ODAs but not total fertilization failure after ICSI

Research questionAre there other variants in DNAH17 related to male infertility? What is the correlation between total fertilization failure and DNAH17 deficiency? DesignWhole-exome sequencing and Sanger sequencing were performed in a cohort of 75 Chinese patients with MMAF to identify potential novel gene variants. Papanicolaou staining and electron microscopy were employed to observe sperm morphology and ultrastructure. Proteomic analysis and comprehensive functional analysis were performed to elucidate the relationship between DNAH17 deficiency and total fertilization failure at the molecular level. ResultsTen novel variants in DNAH17 were identified in five unrelated families with six infertile males. These identified variants exhibited an autosomal recessive inheritance pattern and caused the deficiency of DNAH17 in sperm. Papanicolaou staining and electron microscopy demonstrated typical MMAF characteristics and deformations in flagellar ultrastructure of DNAH17-deficient sperm. Furthermore, our comprehensive functional analysis revealed that DNAH17 deficiency impaired the assembly and docking of ODAs, affected the acrosome reaction, and disrupted mitochondrial function. Interestingly, the fertilization-related proteins such as ACTL7A and PICK1 were normal, while reduced yet ≥30% PLCζ levels were detected, implying an indirect correlation between DNAH17 deficiency and total fertilization failure. Moreover, four of the affected couples got transferable embryos successfully through intracytoplasmic sperm injection (ICSI) without artificial oocyte activation (AOA). ConclusionsOur findings significantly broaden the variant spectrum of DNAH17 and illuminate the complex molecular basis of male infertility associated with DNAH17 deficiency, particularly its heterogeneous impact on fertilization. The favourable fertility outcomes of ICSI will provide vital insights for genetic diagnosis and counselling in males affected by MMAF.

N-glycoproteomic and proteomic alterations in SRD5A3-deficient fibroblasts.

SRD5A3-CDG is a congenital disorder of glycosylation (CDG) resulting from pathogenic variants in SRD5A3 and follows an autosomal recessive inheritance pattern. The enzyme encoded by SRD5A3, polyprenal reductase, plays a crucial role in synthesizing lipid precursors essential for N-linked glycosylation. Despite insights from functional studies into its enzymatic function, there remains a gap in understanding global changes in patient cells. We sought to identify N-glycoproteomic and proteomic signatures specific to SRD5A3-CDG, potentially aiding in biomarker discovery and advancing our understanding of disease mechanisms. Using tandem mass tag (TMT)-based relative quantitation, we analyzed fibroblasts derived from five patients along with control fibroblasts. N-glycoproteomics analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 3,047 glycopeptides with 544 unique N-glycosylation sites from 276 glycoproteins. Of these, 418 glycopeptides showed statistically significant changes with 379 glycopeptides decreased (P<0.05) in SRD5A3-CDG patient-derived samples. These included high mannose, complex and hybrid glycan-bearing glycopeptides. High mannose glycopeptides from protocadherin Fat 4 and integrin alpha-11 and complex glycopeptides from CD55 were among the most significantly decreased glycopeptides. Proteomics analysis led to the identification of 5,933 proteins, of which 873 proteins showed statistically significant changes. Decreased proteins included cell surface glycoproteins, various mitochondrial protein populations and proteins involved in the N-glycosylation pathway. Lysosomal proteins such as N-acetylglucosamine-6-sulfatase and procathepsin-L also showed reduced levels of phosphorylated mannose-containing glycopeptides. Our findings point to disruptions in glycosylation pathways as well as energy metabolism and lysosomal functions in SRD5A3-CDG, providing clues to improved understanding and management of patients with this disorder.

A comprehensive review of Alport syndrome: definition, pathophysiology, clinical manifestations, and diagnostic considerations.

Alport syndrome, a rare genetic disorder affecting around 1 in 50,000 individuals, primarily presents as microscopic hematuria and chronic kidney disease (CKD) with associated extrarenal complications. The Alport syndrome results from mutations in COL4A3, COL4A4, and COL4A5 genes, disrupting the formation of the α3-α4-α5 chain in the collagen IV network. The etiology involves X chromosome-related, autosomal dominant, autosomal recessive, and digenic inheritance patterns. The disease primarily manifests as kidney involvement, featuring persistent hematuria, proteinuria, and a progressive decline in renal function. Hearing loss, ocular abnormalities, and extrarenal manifestations further contribute to its complexity. Genotype-phenotype correlations are relatively evident, with distinct presentations in X-linked, autosomal recessive, and autosomal dominant cases. Diagnosis relies on urinalysis, histologic examination, and genetic testing with advancements in next-generation sequencing aiding identification. Although no specific treatment exists, early diagnosis improves outcomes, emphasizing the importance of genetic testing for prognosis and familial screening. The purpose of this review is to advance knowledge and enhance understanding of Alport syndrome.

Genetic profile of progressive myoclonic epilepsy in Mali reveals novel findings.

Progressive myoclonic epilepsy (PME) is a group of neurological disorders characterized by recurrent myoclonic seizures with progressive neurological deterioration. We investigated the genetics of three unrelated patients with PME from Mali, a country in sub-Saharan Africa highly underrepresented in genetic and genomic research. Participants were carefully examined and phenotyped. DNA was obtained for genetic analysis including whole exome sequencing (WES). In silico prediction tools and ACMG criteria were used to assess the deleteriousness of putative candidate variants. Pedigree analysis suggests autosomal recessive inheritance patterns for one family and sporadic forms of PME for the two other cases. WES identified novel homozygous missense variants in all the three patients, one each for NHLRC1, EPM2A, and NEU1. The sequence variants segregated with PME in each family and in silico studies including protein 3D structures, CADD scores and ACMG criteria suggested that they were damaging. PME is a group of clinically heterogeneous neurological disorders. Most reported cases in the literature are from European background with only a few cases described in North Africa. We report here novel pathogenic variants in three different genes causing PME phenotypes in three unrelated Malian patients, suggesting that genetic studies of underrepresented populations may expand the genetic epidemiology of PME. These findings also emphasize the need for inclusive genetic research to ensure a more targeted diagnostic and therapeutic approaches for diverse patient populations.

Primary ciliary dyskinesia: a case report of double DNAH11 mutant alleles

Primary ciliary dyskinesia (PCD), a rare disorder, is genetically varied. Mutations in proteins involved in the structure, function, or assembly of cilia are known to determine situs inversus, male infertility, and chronic destructive airway disease. PCD is inherited by an autosomal recessive pattern of inheritance in most cases. Nonetheless, patterns of autosomal dominant and X-linked inheritance have been mentioned. A history of recurrent upper and lower respiratory tract infections raised clinical suspicion of primary ciliary dyskinesia in a 10-year-old patient. Genetic tests were performed using next-generation sequencing technology (Illumina NextGen) with the multiplex ligation-dependent probe amplification technique for primary ciliopathies and syndromes subject to differential diagnosis. Genetic testing identified two pathogenic variants, not previously associated with a case report in the literature, c.7727A&gt;G (p.Asp2576Gly) and c.8578G&gt;A (p.Gly2860Ser), within the DNAH11 gene, which is associated with autosomal recessive PCD. The result also reported mutations in other genes involved in autosomal recessive PCD (DNAH8, DNAH9 and ZMYND10), which were classified as variants with uncertain clinical significance. Transmission electron microscopy of respiratory cilia and nasal nitric oxide measurement cannot be used to diagnose PCD in patients with DNAH11 mutations because the structure of cilia is normal, and the levels of NO are not constantly low. High-speed video microscopy analysis can be helpful because DNAH11 mutations cause a distinct phenotype of PCD. Nevertheless, the mutation analysis of various PCD-causing genes remains the easiest to conduct and with good results. Genetic research on PCD has identified a number of significant ciliary genes in recent years, offering fresh perspectives on the molecular processes underlying cilia assembly and function. This facilitates the development of new methods for the diagnosis, prevention, and treatment of PCD. However, because it is a highly complex and heterogeneous disease, the field of gene diagnosis and therapy in PCD is still in its infancy.

McArdle's Disease: A Differential Diagnosis of Metabolic Myopathies.

McArdle's disease, also known as glycogen storage disease type V or McArdle syndrome, is a pure muscle myopathy with an autosomal recessive inheritance pattern. It is caused by mutations in the gene that encodes muscle phosphorylase. Symptoms typically begin in late adolescence or early adulthood, presenting as exercise intolerance. This review focuses on the diagnosis of McArdle's disease, initially manifesting as a clinical picture of rhabdomyolysis in an 18-year-old male patient with a history of minor thalassemia who had been followed in pediatric consultation since age three for failure to thrive. After excluding common causes such as alcohol consumption, drug use, traumatic muscle compression, and other conditions, the diagnosis of McArdle's disease was considered. The diagnosis was supported by laboratory tests showing myoglobinuria and elevated creatine kinase levels, as well as the absence of increased serum lactate following ischemic exercise. Genetic testing confirmed the presence of mutations in the PYGM gene, corroborating the diagnosis. Treatment includes administering a diet rich in slow-absorbing carbohydrates, regular low-intensity physical exercise, and, in some cases, supplementation with vitamin B6 and creatine. The prognosis is generally favorable with proper disease management, although vigorous exercise should be avoided to prevent complications such as severe muscle injury and rhabdomyolysis. Although McArdle's disease is a rare condition, it is likely underdiagnosed. Ideally, it should be considered in the differential diagnosis of rhabdomyolysis in all patients with symptoms of exercise intolerance and/or recurrent myoglobinuria.