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JCI Insight May 2024Patients with autosomal dominant polycystic kidney disease (ADPKD), a genetic disease due to mutations of the PKD1 or PKD2 gene, show signs of complement activation in...
Patients with autosomal dominant polycystic kidney disease (ADPKD), a genetic disease due to mutations of the PKD1 or PKD2 gene, show signs of complement activation in the urine and cystic fluid, but their pathogenic role in cystogenesis is unclear. We tested the causal relationship between complement activation and cyst growth using a Pkd1KO renal tubular cell line and newly generated conditional Pkd1-/- C3-/- mice. Pkd1-deficient tubular cells have increased expression of complement-related genes (C3, C5, CfB, C3ar, and C5ar1), while the gene and protein expression of complement regulators DAF, CD59, and Crry is decreased. Pkd1-/- C3-/- mice are unable to fully activate the complement cascade and are characterized by a significantly slower kidney cystogenesis, preserved renal function, and reduced intrarenal inflammation compared with Pkd1-/- C3+/+ controls. Transgenic expression of the cytoplasmic C-terminal tail of Pkd1 in Pkd1KO cells lowered C5ar1 expression, restored Daf levels, and reduced cell proliferation. Consistently, both DAF overexpression and pharmacological inhibition of C5aR1 (but not C3aR) reduced Pkd1KO cell proliferation. In conclusion, the loss of Pkd1 promotes unleashed activation of locally produced complement by downregulating DAF expression in renal tubular cells. Increased C5a formation and C5aR1 activation in tubular cells promotes cyst growth, offering a new therapeutic target.
Topics: Animals; Polycystic Kidney, Autosomal Dominant; Mice; CD55 Antigens; Complement C3; Mice, Knockout; Receptor, Anaphylatoxin C5a; Disease Models, Animal; Complement Activation; TRPP Cation Channels; Humans; Cell Proliferation; Male; Cell Line; Receptors, Complement 3b
PubMed: 38912583
DOI: 10.1172/jci.insight.175220 -
BMJ Neurology Open 2024Dystonia is a genetic or non-genetic movement disorder with typical patterned and twisting movements due to abnormal muscle contractions that may be associated with...
BACKGROUND
Dystonia is a genetic or non-genetic movement disorder with typical patterned and twisting movements due to abnormal muscle contractions that may be associated with tremor. Genetic and phenotypic heterogeneity leads to variable clinical presentation.
METHODOLOGY
Next-generation sequencing technologies are being currently used in the workup of patients with inherited dystonia to determine the specific cause in the individuals with autosomal dominant, recessive, X-linked or mitochondrial inheritance patterns. Calcium voltage-gated channel subunit alpha1 A (CACNA1A) gene variants are rare in dystonias.
RESULTS
We here present a 20-year-old man with a history of delayed milestones, flexor posturing, dysarthria, dysphagia and a negative family history from consanguineous parents. Neurological examination revealed right lateral scoliosis of the neck and generalised dystonic posturing affecting both upper and lower limbs. MRI of the brain was unremarkable. Molecular genetic results revealed a heterozygous variant in the CACNA1A gene (CHR19: NM_023035.2, c. 1602G>A; p. Met534Ile). Segregation analyses in both the parents revealed wild-type CACNA1A gene suggesting de novo nature of the variant with a likely pathogenic classification.
CONCLUSION
Dystonia is one of the clinical phenotypes that can be associated with CACNA1A gene mutations and we recommend that this gene either be included in the dystonia panel offered or tested when the initial primary genetic result is negative.
PubMed: 38912174
DOI: 10.1136/bmjno-2024-000710 -
Cureus Jun 2024Wilson's disease (WD) is an autosomal recessive disorder that impairs copper metabolism. Copper accumulates in vital organs such as the brain, liver, and kidneys. The...
Wilson's disease (WD) is an autosomal recessive disorder that impairs copper metabolism. Copper accumulates in vital organs such as the brain, liver, and kidneys. The disease typically starts with copper accumulation in the liver and can initially present as acute hepatitis and hepatomegaly. Hemolytic anemia is a typically uncommon complication of WD. We present the case of a healthy 18-year-old female who presented with hemolytic anemia and quickly decompensated to fulminant hepatic failure requiring a liver transplant due to previously undiagnosed WD. This case recognizes the importance of early diagnosis as treatment can be lifesaving.
PubMed: 38912076
DOI: 10.7759/cureus.62966 -
Frontiers in Neuroscience 2024Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare incurable neurodegenerative disease caused by mutations in the gene, which codes for...
INTRODUCTION
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare incurable neurodegenerative disease caused by mutations in the gene, which codes for sacsin, a large protein involved in protein homeostasis, mitochondrial function, cytoskeletal dynamics, autophagy, cell adhesion and vesicle trafficking. However, the pathogenic mechanisms underlying sacsin dysfunction are still largely uncharacterized, and so attempts to develop therapies are still in the early stages.
METHODS
To achieve further understanding of how processes are altered by loss of sacsin, we used untargeted proteomics to compare protein profiles in ARSACS fibroblasts versus controls.
RESULTS
Our analyses confirmed the involvement of known biological pathways and also implicated calcium and lipid homeostasis in ARSACS skin fibroblasts, a finding further verified in SH-SY5Y cells. Validation through mass spectrometry-based analysis and comparative quantification of lipids by LC-MS in fibroblasts revealed increased levels of ceramides coupled with a reduction of diacylglycerols.
DISCUSSION
In addition to confirming aberrant Ca homeostasis in ARSACS, this study described abnormal lipid levels associated with loss of sacsin.
PubMed: 38911600
DOI: 10.3389/fnins.2024.1375299 -
Tremor and Other Hyperkinetic Movements... 2024Spinocerebellar ataxia (SCA) denotes an expanding list of autosomal dominant cerebellar ataxias. Although tremor is an important aspect of the clinical spectrum of the... (Review)
Review
BACKGROUND
Spinocerebellar ataxia (SCA) denotes an expanding list of autosomal dominant cerebellar ataxias. Although tremor is an important aspect of the clinical spectrum of the SCAs, its prevalence, phenomenology, and pathophysiology are unknown.
OBJECTIVES
This review aims to describe the various types of tremors seen in the different SCAs, with a discussion on the pathophysiology of the tremors, and the possible treatment modalities.
METHODS
The authors conducted a literature search on PubMed using search terms including tremor and the various SCAs. Relevant articles were included in the review after excluding duplicate publications.
RESULTS
While action (postural and intention) tremors are most frequently associated with SCA, rest and other rare tremors have also been documented. The prevalence and types of tremors vary among the different SCAs. SCA12, common in certain ethnic populations, presents a unique situation, where the tremor is typically the principal manifestation. Clinical manifestations of SCAs may be confused with essential tremor or Parkinson's disease. The pathophysiology of tremors in SCAs predominantly involves the cerebellum and its networks, especially the cerebello-thalamo-cortical circuit. Additionally, connections with the basal ganglia, and striatal dopaminergic dysfunction may have a role. Medical management of tremor is usually guided by the phenomenology and associated clinical features. Deep brain stimulation surgery may be helpful in treatment-resistant tremors.
CONCLUSIONS
Tremor is an elemental component of SCAs, with diverse phenomenology, and emphasizes the role of the cerebellum in tremor. Further studies will be useful to delineate the clinical, pathophysiological, and therapeutic aspects of tremor in SCAs.
Topics: Humans; Tremor; Spinocerebellar Ataxias; Deep Brain Stimulation
PubMed: 38911333
DOI: 10.5334/tohm.911 -
Indian Journal of Endocrinology and... 2024Congenital adrenal hyperplasia (CAH) comprises a heterogeneous group of autosomal recessive disorders impairing adrenal steroidogenesis. Most cases are caused by... (Review)
Review
Congenital adrenal hyperplasia (CAH) comprises a heterogeneous group of autosomal recessive disorders impairing adrenal steroidogenesis. Most cases are caused by mutations in the gene resulting in 21-hydroxylase (21-OH) deficiency (21-OHD). The genetics of 21-OH CAH is complexed by a highly homologous pseudogene imposing several limitations in the molecular analysis. Therefore, genetic testing is still not a part of routine CAH diagnosis and is mainly dependent on 17-hydroxy progesterone (OHP) measurements. There are very few reports of gene analysis from India and there is no comprehensive review available on genetic testing and the spectrum of mutations from the country. This review focuses on the molecular aspects of 21-OHD and the genetic studies on gene reported from India. The results of these studies insist the compelling need for large-scale genetic testing and newborn screening (NBS) in India. With a high disease prevalence and consanguinity rates, robust and cost-effective genetic testing for 21-OH CAH would enable an accurate diagnosis in routine clinical practice. Whereas establishing affordable genotyping assays even in secondary care or resource-poor settings of the country can identify 90% of the mutations that are pseudogene derived, initiatives on reference laboratories for CAH across the nation with comprehensive genetic testing facilities will be beneficial in those requiring extended analysis of gene. Further to this, incorporating genetic testing in NBS and carrier screening programmes will enable early diagnosis, better risk assessment and community-based management.
PubMed: 38911104
DOI: 10.4103/ijem.ijem_303_23 -
Journal of Orthopaedic Case Reports Jun 2024Alkaptonuria is a rare autosomal recessive genetic disorder found in 2-5/million live births. It results in dark brown pigmentation of connective tissues including...
INTRODUCTION
Alkaptonuria is a rare autosomal recessive genetic disorder found in 2-5/million live births. It results in dark brown pigmentation of connective tissues including cartilage and joint capsule that can often lead to arthropathy of large joints. However, bone fractures are unusual. This article describes a fracture neck of the femur in a patient with undiagnosed alkaptonuria managed at a rural center.
CASE REPORT
A 60-year-old daily wage laborer with previously pain-free hips presented with sudden onset pain in the left hip while walking with no prior history of trauma. Radiographs showed a displaced fracture of the neck of the left femur. She underwent Left hip hemiarthroplasty. Intraoperatively, her soft-tissue including the joint capsule and the femoral head had dark brown pigmentation. Postoperatively, her urine was tested and the same turned black supporting the clinical diagnosis of alkaptonuria. At her 1-year follow-up, she had a painless, stable, and mobile hip.
CONCLUSION
We report a rare and unique case of neck of femur fracture in a patient with alkaptonuria treated with hemiarthroplasty in a resource-limited hospital in rural India. It is essential to consider the possibility of this condition when we come across a patient with an atypical fracture presentation. This article also presents an overview of alkaptonuria with a discussion on etiopathogenesis, clinical presentation, diagnosis, and management.
PubMed: 38910974
DOI: 10.13107/jocr.2024.v14.i06.4508 -
Proceedings (Baylor University. Medical... 2024Lymphangioleiomyomatosis is a rare progressive disease characterized by abnormal smooth muscle cell proliferation leading to a diffuse cystic lung disease and...
Lymphangioleiomyomatosis is a rare progressive disease characterized by abnormal smooth muscle cell proliferation leading to a diffuse cystic lung disease and extrapulmonary manifestations. Most cases are caused by mutations in the and/or genes, which are also associated with tuberous sclerosis complex. We describe a case of sporadic lymphangioleiomyomatosis with autosomal dominant polycystic kidney disease and renal angiolipomas in a patient who tested negative for gene mutations on the and gene panel.
PubMed: 38910798
DOI: 10.1080/08998280.2024.2334629 -
Cureus May 2024Cyclin-dependent kinase 13 (CDK13)-related disorder is a rare autosomal dominant disease caused by pathogenic variants in the gene. This disorder was found to be...
Cyclin-dependent kinase 13 (CDK13)-related disorder is a rare autosomal dominant disease caused by pathogenic variants in the gene. This disorder was found to be related to several clinical features, including structural cardiac anomalies, developmental delay, anomalies of the corpus callosum, and a variety of facial dysmorphisms. In addition, feeding difficulties and neonatal hypotonia might also present. The diagnosis of this disorder is based on molecular genetic testing to detect the causative pathogenic variants. Here, we report a case of a one-year-old girl from Yemen, residing in Bahrain, with a CDK13-related disorder who was found to have an unusual association of abdominal situs inversus along with multiple structural cardiac anomalies, including atrial septal defect, ventricular septal defect, patent ductus arteriosus, interrupted inferior vena cava, bilateral superior vena cava, mild coarctation of the aorta, dilated coronary sinuses, and mild regurgitation in the tricuspid valve. Moreover, facial dysmorphism including medial epicanthal folds, posteriorly rotated ears, and a depressed nasal bridge was also noted. Further assessment showed a delay in reaching developmental milestones, including speech and motor delay. The patient also presented with recurrent episodes of upper respiratory tract infections, acute bronchiolitis, and lobar pneumonia which required admission to the intensive care unit and ventilation. The last infection episode was at the age of one year. Thereafter, the patient underwent cardiac repair of the ventricular septal defect followed by no more infection episodes until the age of one year and two months. The diagnosis of CDK13 was confirmed by a whole exome sequencing test which demonstrated a novel missense variant in exon 14 of the gene as a variant of uncertain significance in a heterozygous state.
PubMed: 38910624
DOI: 10.7759/cureus.60970 -
Neuroscience Letters Jun 2024Huntington's disease (HD) is an autosomal inherited progressive neurodegenerative disorder which is caused by the CAG trinucleotide repeat in the huntingtin gene. The...
Huntington's disease (HD) is an autosomal inherited progressive neurodegenerative disorder which is caused by the CAG trinucleotide repeat in the huntingtin gene. The mutation induces mitochondrial dysfunction in neurons, which leads to striatal neuronal loss. The efficacy of the available therapies is limited, thus acquisition of more data about the pathomechanism of HD and development of new strategies is urgent. Sirtuins (Sirt1-7) belong to the histone deacetylase family, and interestingly they have been associated with HD, however, their role in HD is still not fully understood. To clarify the role of sirtuins in HD, we utilized a 3-nitropropionic acid (3-NP) induced HD model and assessed alterations in gene expression using RT-PCR. Moreover, we studied the extension of neurodegeneration in the striatum, and behavioural changes. Furthermore, we involved Sirt3 knockout (Sirt3KO) mice to investigate the impact of Sirt3 deficiency in the expression of the other sirtuins. Our results showed that with 3-NP treatment, the mRNA level of Sirt2,5,7 changed significantly in wild-type (WT) mice, whereas in Sirt3KO animals there was no change. Interestingly, Sirt3 deficiency did not exacerbate 3-NP-mediated striatal neuronal loss, while Sirt3KO animals showed higher mortality than WT littermates. However, the absence of Sirt3 did not affect the behaviour of animals. Finally, we demonstrated that the changes in the expression of sirtuins are age- and sex- dependent. According to our findings, there is evidence that Sirt3 has a major impact on the regulation of other sirtuin isoforms, survival and neuroprotection. However, this neuroprotective effect does not manifest in the behaviour.
PubMed: 38909839
DOI: 10.1016/j.neulet.2024.137882