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Impaired Autophagic Clearance with a Gain-of-Function Variant of the Lysosomal Cl/H Exchanger ClC-7.Biomolecules Dec 2023ClC-7 is a ubiquitously expressed voltage-gated Cl/H exchanger that critically contributes to lysosomal ion homeostasis. Together with its β-subunit Ostm1, ClC-7...
ClC-7 is a ubiquitously expressed voltage-gated Cl/H exchanger that critically contributes to lysosomal ion homeostasis. Together with its β-subunit Ostm1, ClC-7 localizes to lysosomes and to the ruffled border of osteoclasts, where it supports the acidification of the resorption lacuna. Loss of ClC-7 or Ostm1 leads to osteopetrosis accompanied by accumulation of storage material in lysosomes and neurodegeneration. Interestingly, not all osteopetrosis-causing mutations from patients are associated with a loss of ion transport. Some rather result in an acceleration of voltage-dependent ClC-7 activation. Recently, a gain-of-function variant, ClC-7, that yields larger ion currents upon heterologous expression, was identified in two patients with neurodegeneration, organomegaly and albinism. However, neither the patients nor a mouse model that carried the equivalent mutation developed osteopetrosis, although expression of ClC-7 induced the formation of enlarged intracellular vacuoles. Here, we investigated how, in transfected cells with mutant ClC-7, the substitution of this tyrosine impinged on the morphology and function of lysosomes. Combinations of the tyrosine mutation with mutations that either uncouple Cl from H counter-transport or strongly diminish overall ion currents were used to show that increased ClC-7 Cl/H exchange activity is required for the formation of enlarged vacuoles by membrane fusion. Degradation of endocytosed material was reduced in these compartments and resulted in an accumulation of lysosomal storage material. In cells expressing the ClC-7 gain-of-function mutant, autophagic clearance was largely impaired, resulting in a build-up of autophagic material.
Topics: Mice; Animals; Humans; Osteopetrosis; Gain of Function Mutation; Mutation; Lysosomes; Tyrosine; Chloride Channels
PubMed: 38136669
DOI: 10.3390/biom13121799 -
BMC Oral Health Nov 2023Osteopetrosis comprises a group of inherited disorders that are rare and result in abnormal bone structure. Bone remodeling is extremely inhibited because osteoclasts...
Successful complete oral rehabilitation of a patient with osteopetrosis with extensive pre-treatments, bone grafts, dental implants and fixed bridges: a multidisciplinary case report.
BACKGROUND
Osteopetrosis comprises a group of inherited disorders that are rare and result in abnormal bone structure. Bone remodeling is extremely inhibited because osteoclasts are nonfunctional or lacking. This condition causes overgrowth of bone with disappearance of the bone marrow, leading to aplastic anemia; obstruction of nerve passages in the skull leads to blindness and often hearing impairment. In most cases, osteopetrosis results in oral complications such as tooth deformation, hypomineralization, and delayed or absent tooth eruption. The only curative treatment is hematopoietic stem cell transplantation (HSCT). The main treatment of the oral complications during childhood and adolescence consists in protecting the erupted teeth against caries disease through prophylactic treatment aimed at optimal oral hygiene through frequent regular dental visits throughout life. Many patients with osteopetrosis require major oral rehabilitation to treat complications of the disease. Improved results of HSCT increase the likelihood that dental professionals will encounter patients with osteopetrosis.
CASE PRESENTATION
In this case report, we show that individuals with osteopetrosis who have severe oral complications can be treated successfully if they are treated for osteopetrosis at an early age. The boy had his dental care in pedodontics, and regular multidisciplinary meetings were held for future treatment planning. At the age of 15, he was then referred for rehabilitation. The initial evaluations revealed no further growth in the alveolar bone. The rehabilitation was done stepwise, with extraction of malformed and malpositioned teeth. Initially, the patient received a removable partial denture followed by reconstruction of the width of the alveolar process, titanium implants, temporary fixed bridges, and finally screw-retained titanium-ceramic bridges with titanium frames for the upper and lower jaws.
CONCLUSIONS
The three-year follow-up after loading indicated a stable marginal bone level and optimal oral hygiene as a result of frequent professional oral hygiene care. The patient showed no signs of symptoms from the temporomandibular joint and has adapted to the new jaw relation without any functional or phonetical issues.
Topics: Male; Adolescent; Humans; Dental Implants; Osteopetrosis; Titanium; Dental Caries; Tooth Abnormalities; Denture, Partial, Fixed; Dental Prosthesis, Implant-Supported
PubMed: 38017429
DOI: 10.1186/s12903-023-03707-3 -
Scientific Reports Nov 2023Osteoclasts uniquely resorb calcified bone matrices. To exert their function, mature osteoclasts maintain the cellular polarity and directional vesicle trafficking to...
Osteoclasts uniquely resorb calcified bone matrices. To exert their function, mature osteoclasts maintain the cellular polarity and directional vesicle trafficking to and from the resorbing bone surface. However, the regulatory mechanisms and pathophysiological relevance of these processes remain largely unexplored. Bone histomorphometric analyses in Ccr5-deficient mice showed abnormalities in the morphology and functional phenotype of their osteoclasts, compared to wild type mice. We observed disorganized clustering of nuclei, as well as centrosomes that organize the microtubule network, which was concomitant with impaired cathepsin K secretion in cultured Ccr5-deficient osteoclasts. Intriguingly, forced expression of constitutively active Rho or Rac restored these cytoskeletal phenotypes with recovery of cathepsin K secretion. Furthermore, a gene-disease enrichment analysis identified that PLEKHM1, a responsible gene for osteopetrosis, which regulates lysosomal trafficking in osteoclasts, was regulated by CCR5. These experimental results highlighted that CCR5-mediated signaling served as an intracellular organizer for centrosome clustering in osteoclasts, which was involved in the pathophysiology of bone metabolism.
Topics: Animals; Mice; Bone and Bones; Bone Matrix; Bone Resorption; Cathepsin K; Centrosome; Osteoclasts; Receptors, CCR5
PubMed: 38012303
DOI: 10.1038/s41598-023-48140-2 -
International Journal of Surgery Case... Dec 2023Osteopetrosis is a rare genetic disorder characterized by increased bone density. This condition is clinically manifested with a brittle intramedullary structure and...
INTRODUCTION
Osteopetrosis is a rare genetic disorder characterized by increased bone density. This condition is clinically manifested with a brittle intramedullary structure and reduced bone toughness, increasing the risk of fracture. A limited case has been reported on the management of physeal fracture in patients with osteopetrosis. The objective of this study is to report a rare osteopetrosis patient who sustains Salter-Harris II at the distal tibia with its long-term follow-up along with its literature review.
PRESENTATION OF CASE
We report a case of a four-year-old boy with an established a diagnosis of osteopetrosis brought by the parents to the emergency department after sustaining a fall while playing in the playground. Radiological examination revealed a Salter-Harris type II distal tibial fracture. The patient underwent closed reduction and fixation using the cannulated screw. 18-month postoperative patients have an uneventful healing.
DISCUSSION
Osteopetrosis is caused by impaired osteoclast function and differentiation, leading to impaired in remodelling. Salter-Harris type II distal tibial fracture can be treated by either closed reduction or open reduction. A closed reduction was performed successfully with cannulated screw in his patient.
CONCLUSION
There is a delayed union of fracture in osteopetrosis patient. This will increase the risk of displacement which will eventually resulted in growth disturbance. Delayed weight bearing and stable fixation is highly recommended.
PubMed: 38007865
DOI: 10.1016/j.ijscr.2023.109090 -
Access Microbiology 2023() is a Gram-positive coccus of the family . It can be found in a variety of vegetables and dairy products. is an opportunistic pathogen with intrinsic resistance to...
() is a Gram-positive coccus of the family . It can be found in a variety of vegetables and dairy products. is an opportunistic pathogen with intrinsic resistance to vancomycin and teicoplanin. In this case report, we discuss a rare case of -associated bacteraemia in a patient with osteopetrosis. A 4-year-old girl was admitted to the paediatric emergency department with acute fever without other signs. Blood culture revealed an infection with . Using the streptococcus antibiogram, the isolate was resistant to vancomycin, teicoplanin, rifampicin and sulfamethoxazole-trimethoprim but sensitive to β-lactams, gentamicin, streptomycin, azithromycin, clarithromycin, lincomycin, clindamycin and erythromycin. The patient was treated with intravenous ceftriaxone and gentamicin, and subsequently with oral amoxicillin. After a favourable course, she was discharged from the hospital on the 10th day. The modes of transmission and physiopathology of remain unknown. Factors associated with this infection include compromised immunity, previous antibiotic therapy especially with vancomycin, and application of a central venous catheter. In our patient, the risk factors for infection were pancytopenia and multiple transfusions used to treat bone marrow failure. The source of the bacteraemia could have been the cutaneous route, but it could also have been digestive due to the reservoir of the bacteria. is known as an opportunistic bacterium. Further studies on its pathogenesis and other risk factors are needed to understand the true prevalence of this potentially fatal bacterium in compromised individuals, such as the case of our patient.
PubMed: 37970073
DOI: 10.1099/acmi.0.000439 -
Surgical Neurology International 2023Osteopetrosis is a rare disease characterized by systemic osteosclerosis and hematopoietic disturbances. Childhood-onset cases are often accompanied by hydrocephalus and...
BACKGROUND
Osteopetrosis is a rare disease characterized by systemic osteosclerosis and hematopoietic disturbances. Childhood-onset cases are often accompanied by hydrocephalus and craniosynostosis; however, there have been no established treatments. We performed cranial distraction in a child with osteopetrosis who presented with craniosynostosis and intracranial hypertension.
CASE DESCRIPTION
The patient was a 4-year-1-month-old boy. His pregnancy and birth were normal, but at 4 months of age, he was diagnosed with osteopetrosis based on generalized osteosclerosis and family history. A computed tomography scan of the head revealed early sagittal suture fusion and ventricular enlargement. A ventriculoperitoneal shunt was placed for intracranial hypertension; however, slit ventricle syndrome ensued and pansynostosis developed. To improve uncontrolled high intracranial pressure, cranial distraction was performed for intracranial volume expansion. No perioperative hemorrhagic or infectious complications were observed. After the start of distraction, the intracranial pressure gradually decreased, and clinical findings such as disturbance of consciousness and bradycardia disappeared. Bone regeneration in the defect site was good, and the extension device was removed 6 months after the operation.
CONCLUSION
For osteopetrosis with poorly controlled intracranial hypertension, cranial distraction was considered to be an effective treatment.
PubMed: 37941624
DOI: 10.25259/SNI_623_2023 -
Frontiers in Endocrinology 2023Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of...
BACKGROUND
Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of osteosclerosis of the metaphyseal margins of long tubular bones. To date, only thirteen cases have been reported (eight molecularly confirmed). Five homozygous sequence variants in the leucine-rich repeat kinase 1 () gene have been identified to cause OSMD. We present two male siblings with OSMD with a novel variant.
CASES
The index case, now aged 6 years, was referred aged 9 months when diffuse sclerosis of the ribs and vertebral bodies, suggestive of osteopetrosis, was incidentally identified on a chest radiograph for suspected lower respiratory tract infection. Parents were consanguineous and of Pakistani origin. Further evaluation revealed developmental delay, nystagmus with bilateral optic nerve hypoplasia and severe visual impairment. Skeletal survey confirmed typical changes of OSMD, with widespread diffuse sclerosis and Erlenmeyer flask deformity of long bones. His older sibling, now aged 12 years, was 7 years at the time of referral and had similar clinical course and skeletal findings. Additionally, he had a chronic progressive osteonecrosis of the left mandible that required debridement, debulking and long-term antibiotics. Skeletal survey revealed findings similar to his sibling. Neither sibling had significant skeletal fractures or seizures. Unlike most previous reports suggesting sparing of the skull and lack of visual impairment, our patients had evidence of osteosclerosis of the cranium. Genetic screening for the common autosomal recessive and dominant pathogenic variants of osteopetrosis was negative. Whole Exome Sequencing (WES) followed by Sanger sequencing, identified a novel homozygous c.2506C>T p. (Gln836Ter) nonsense variant predicted to result in premature truncation of LRRK1 transcript.
CONCLUSION
Our cases confirm the autosomal recessive inheritance and expand the spectrum of genotype and phenotype of OSMD reported in the literature. Increasing reports of variants in this phenotype raise the question of whether should be included in targeted osteopetrosis panels. Bone histology in previous cases has shown this to be an osteoclast rich form of osteopetrosis raising the possibility that haematopoietic stem cell transplantation may be an appropriate treatment modality.
Topics: Humans; Male; Mutation; Optic Nerve; Osteopetrosis; Osteosclerosis; Protein Serine-Threonine Kinases; Ribs; Sclerosis; Vision Disorders; Child
PubMed: 37920250
DOI: 10.3389/fendo.2023.1258340 -
Pediatric Health, Medicine and... 2023Leukoerythroblastosis is rarely encountered in clinical practice and is characterized by the presence of leukocytosis and erythroid and myeloid blast cells in peripheral...
Leukoerythroblastosis is rarely encountered in clinical practice and is characterized by the presence of leukocytosis and erythroid and myeloid blast cells in peripheral blood. The most common causes of leukoerythroblastosis in early childhood are viral infection, juvenile myelomonocytic leukemia, and osteopetrosis. To the best of our knowledge, leukoerythroblastic reactions associated with hemolysis have not been previously reported in newborns. Here, we report a 24-hour-old female term newborn diagnosed with a leukoerythroblastic reaction, severe anemia, and neonatal hyperbilirubinemia secondary to Rh incompatibility based on presentation, laboratory determination, and peripheral morphology. A high index of clinical suspicion is required to avoid life-threatening complications among health professionals in the neonatal care unit.
PubMed: 37872980
DOI: 10.2147/PHMT.S430828 -
International Journal of Molecular... Sep 2023Osteopetrosis is a rare inherited disease caused by osteoclast failure, resulting in increasing bone density in humans. Patients with osteopetrosis possess several...
Osteopetrosis is a rare inherited disease caused by osteoclast failure, resulting in increasing bone density in humans. Patients with osteopetrosis possess several dental and cranial complications. Since carbonic anhydrase II (CA-II) deficiency is a major cause of osteopetrosis, CA-II activators might be an attractive potential treatment option for osteopetrosis patients. We conducted comprehensive label-free quantitative proteomics analysis on Fluconazole-treated Dental Pulp Mesenchymal Stem/Stromal Cells from CA-II-Deficient Osteopetrosis Patients. We identified 251 distinct differentially expressed proteins between healthy subjects, as well as untreated and azole-treated derived cells from osteopetrosis patients. Twenty-six (26) of these proteins were closely associated with osteogenesis and osteopetrosis disease. Among them are ATP1A2, CPOX, Ap2 alpha, RAP1B and some members of the RAB protein family. Others include AnnexinA1, 5, PYGL, OSTF1 and PGAM4, all interacting with OSTM1 in the catalytic reactions of HCO3 and the Cl- channel via CAII regulation. In addition, the pro-inflammatory/osteoclast regulatory proteins RACK1, MTSE, STING1, S100A13, ECE1 and TRIM10 are involved. We have identified proteins involved in osteogenic and immune metabolic pathways, including ERK 1/2, phosphatase and ATPase, which opens the door for some CA activators to be used as an alternative drug therapy for osteopetrosis patients. These findings propose that fluconazole might be a potential treatment agent for CAII- deficient OP patients. Altogether, our findings provide a basis for further work to elucidate the clinical utility of azole, a CA activator, as a therapeutic for OP.
Topics: Humans; Fluconazole; Osteogenesis; Dental Pulp; Osteopetrosis; Azoles; Metabolic Networks and Pathways; Mesenchymal Stem Cells; rap GTP-Binding Proteins
PubMed: 37762144
DOI: 10.3390/ijms241813841 -
Orphanet Journal of Rare Diseases Sep 2023Skeletal dysplasias are a diverse group of rare disorders in the chondro-osseous tissue that can have a significant impact on patient's functionality. The worldwide...
BACKGROUND
Skeletal dysplasias are a diverse group of rare disorders in the chondro-osseous tissue that can have a significant impact on patient's functionality. The worldwide prevalence of skeletal dysplasias at birth is approximately 1:5000 births. To date, disease burden and trends of skeletal dysplasias in the Sri Lankan population have not been described in any epidemiological study. Our aim was to evaluate the burden and the current trends in hospital admissions for skeletal dysplasias in the Sri Lankan population. A retrospective evaluation of hospital admissions for skeletal dysplasia during 2017-2020 was performed using population-based data from the eIMMR database which covers government hospitals in the entire country. The trends in hospital admissions for skeletal dysplasias by calendar year, age, and types of skeletal dysplasia were described using appropriate summary statistics.
RESULTS
Respective crude admission rates of skeletal dysplasias in the years 2017, 2018, 2019 and 2020 were 5.2, 8.1, 8.0, and 6.5 per million population. A female predominance (1.4:1) was noted during the studied period. Of all reported cases the majority (n = 268; 44.2%) were children less than 4 years. Each year, 0-4 years age group represented 40-47% of the total hospital admissions. More than half of the cases were reported from Colombo (28.1%) and Kandy (25.4%) districts combined. 60% of cases were diagnosed as osteogenesis imperfecta (OI). Rising trends were observed in the hospital admissions for osteogenesis imperfecta, achondroplasia and osteopetrosis, while other skeletal dysplasia types collectively showed a relatively stable trend.
CONCLUSION
This preliminary study revealed a female predominance of skeletal dysplasias and a relatively high admission rate of osteogenesis imperfecta in the Sri Lankan population. A distinct trend was not visible in the studied years probably due to the impact on hospital services due to COVID- Pandemic. Future research on the healthcare burden on families affected by skeletal dysplasia is required to better understand the overall cost of care and identify therapies that reduce admission rates. This study highlights the value of analysing population-based data on rare diseases to improve healthcare in low-resource countries.
Topics: Infant, Newborn; Child; Female; Humans; Male; Osteogenesis Imperfecta; Sri Lanka; Retrospective Studies; COVID-19; Osteochondrodysplasias; Hospitals
PubMed: 37684696
DOI: 10.1186/s13023-023-02884-2