Low Syndrome Research Articles

Deformities in reared cobia, Rachycentron canadum L. and grouper, Epinephelus marginatus, in São Paulo state coast, Brazil: case report

ABSTRACT Skeletal deformities are frequent problems in cultured fish populations due mainly to unfavorable abiotic conditions, inappropriate nutrition, and genetic factors. These may cause erratic swimming, decrease of conversion rate, growth, and market value. The aim of this case report was to present the occurrence of deformities in juvenile cobia and groupers from an offshore marine farm in Ilhabela, São Paulo, Brazil. Nine cobias and seven juvenile groupers, that presented deformities, were euthanized and fixed in 10% formaldehyde. They were tagged, processed, and stained with "Alcian Blue" (AB) and "Alizarin Red-S" (ARS) for visualization of cartilage and bone tissue, respectively. After evisceration, radiographic examination was performed. The deformities observed in cobia were atrophy of the operculum, disorganization of the gill lamellae, deformity of the lower jaw, kyphosis, and scoliosis. Groupers presented lower jaw deformity and saddleback syndrome. The farm studied in this case report had poor management standards, fed commercial feed for freshwater herbivorous fish and cooked sardines, high inbreeding and absence of adequately trained professionals to manage these species. The sum of these factors must have directly influenced the appearance of these deformities. It is necessary to control this situation to minimize the incidence of malformations that have economic impacts to farmers.

Quantitative Imaging Flow Cytometry of Legionella-Infected Dictyostelium Amoebae Reveals the Impact of Retrograde Trafficking on Pathogen Vacuole Composition.

The ubiquitous environmental bacterium Legionella pneumophila survives and replicates within amoebae and human macrophages by forming a Legionella-containing vacuole (LCV). In an intricate process governed by the bacterial Icm/Dot type IV secretion system and a plethora of effector proteins, the nascent LCV interferes with a number of intracellular trafficking pathways, including retrograde transport from endosomes to the Golgi apparatus. Conserved retrograde trafficking components, such as the retromer coat complex or the phosphoinositide (PI) 5-phosphatase D. discoideum 5-phosphatase 4 (Dd5P4)/oculocerebrorenal syndrome of Lowe (OCRL), restrict intracellular replication of L. pneumophila by an unknown mechanism. Here, we established an imaging flow cytometry (IFC) approach to assess in a rapid, unbiased, and large-scale quantitative manner the role of retrograde-linked PI metabolism and actin dynamics in the LCV composition. Exploiting Dictyostelium discoideum genetics, we found that Dd5P4 modulates the acquisition of fluorescently labeled LCV markers, such as calnexin, the small GTPase Rab1 (but not Rab7 and Rab8), and retrograde trafficking components (Vps5, Vps26, Vps35). The actin-nucleating protein and retromer interactor WASH (Wiskott-Aldrich syndrome protein [WASP] and suppressor of cAMP receptor [SCAR] homologue) promotes the accumulation of Rab1 and Rab8 on LCVs. Collectively, our findings validate IFC for the quantitative and unbiased analysis of the pathogen vacuole composition and reveal the impact of retrograde-linked PI metabolism and actin dynamics on the LCV composition. The IFC approach employed here can be adapted for a molecular analysis of the pathogen vacuole composition of other amoeba-resistant pathogens.IMPORTANCELegionella pneumophila is an amoeba-resistant environmental bacterium which can cause a life-threatening pneumonia termed Legionnaires' disease. In order to replicate intracellularly, the opportunistic pathogen forms a protective compartment, the Legionella-containing vacuole (LCV). An in-depth analysis of the LCV composition and the complex process of pathogen vacuole formation is crucial for understanding the virulence of L. pneumophila Here, we established an imaging flow cytometry (IFC) approach to assess in a rapid, unbiased, and quantitative manner the accumulation of fluorescently labeled markers and probes on LCVs. Using IFC and L. pneumophila-infected Dictyostelium discoideum or defined mutant amoebae, a role for phosphoinositide (PI) metabolism, retrograde trafficking, and the actin cytoskeleton in the LCV composition was revealed. In principle, the powerful IFC approach can be used to analyze the molecular composition of any cellular compartment harboring bacterial pathogens.

The Spectrum of Kidney Diseases in Children Associated with Low Molecular Weight Proteinuria.

BACKGROUND:Proteinuria, in addition to haematuria, is the most important laboratory parameter in patients with nephro-urological diseases. Low molecular weight proteinuria (LMWP) is of particular importance because some diseases genetic and tubulointerstitial are diagnosed based on its presence.AIM:The purpose of this study is to describe the clinical features, the course and outcome of pediatric patients with a renal disease associated with LMWP.MATERIAL AND METHODS:This retrospective observational study included 250 pediatric patients with various kidney diseases in which the type of proteinuria was defined by 4-20% gradient gel sodium dodecyl sulphate polyacrylamide gel (SDS-PAG) electrophoresis.RESULTS:Isolated LMWP was detected in 12% of patients, while mixed glomerulotubular proteinuria was detected in 18% of patients. It was detected in all patients with the Dent-1/2 disease, Lowe’s syndrome and secondary Fanconi syndrome. Transient LMWP was also detected in a series of 12 patients with distal renal tubular acidosis. In patients with nephrotic syndrome, it was associated with corticoresistence and unfavourable clinical course.CONCLUSION:This study contributes to the understanding of the clinical spectrum of various kidney diseases associated with LMWP, their natural course, and the effect of therapy.

Differential effect of OCRL1 patient mutations on protein localization, and sensitivity to FDA‐approved drug suppression of cellular phenotypes associated with Lowe syndrome

Lowe Syndrome (LS) is a lethal X‐linked genetic disorder caused by mutations in the OCRL1 gene, which encodes the lipid phosphatase Ocrl1. LS children present with congenital cataracts, low molecular weight proteinuria and mental retardation as characteristic clinical symptoms. Progressive renal dysfunction is the main cause of death. Ocrl1 localizes to the trans Golgi network (TGN), early endosomes and the plasma membrane and has been shown to participate in vesicle trafficking. We established that LS patient cells are defective in fluid phase uptake and ciliogenesis, which are critical processes required for kidney function. Over 100 OCRL1 mutations have been identified in LS, but their specific impact on cellular processes is unknown. However, our results indicate that different mutations have diverse effect on Ocrl1 localization and on triggering cellular phenotypes.We expressed GFP‐Ocrl1 (WT and several patient mutants) in human kidney proximal tubule (HK2) cells and LS fibroblasts lacking endogenous Ocrl1. The co‐localization of WT/mutant Ocrl1 with various organelle markers was quantitatively analyzed and different cellular processes/phenotypes were monitored. Our data indicates that in general, N‐terminal PH domain mutations resulted in redistribution of Ocrl1 to the cytoplasm, ASH‐RhoGAP domain mutations prevented localization of Ocrl1 to TGN and mutations in the phosphatase domain resulted in Golgi apparatus (GA) morphological abnormalities.Importantly, using a drug repurposing approach we identified two FDA‐approved compounds able to differentially suppress LS cellular phenotypes; the ability of these drugs to alleviate defects associated with specific Ocrl1 patient mutants was also analyzed. Our data indicate that while some patient OCRL1 mutations require treatment with both drugs, others only necessitate one for LS cellular phenotype suppression.This study determined for the first time the effect of different patient mutation on the Ocrl1 intracellular localization and on various LS‐associated cellular phenotypes. Further, it explored how different OCRL1 mutations determined the sensitivity of cells to the newly identified FDA‐approved drugs with ameliorating effects on LS phenotypes. It also contributes to expand our understanding of the molecular mechanism of LS pathogenesis and provide the basis for the development of a LS‐specific therapeutic.Support or Funding InformationLowe Syndrome TrustNational Institutes of Health (NIH)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The oculocerebrorenal syndrome of Lowe protein (OCRL) inhibits the Na/bicarbonate cotransporter NBCe1 expressed in Xenopus laevis oocytes.

The electrogenic Na/HCO3 cotransporter NBCe1 regulates intracellular pH in many tissues and contributes to solute reabsorption/secretion in epithelia. NBCe1 is modulated by hormones, classic second messengers, and other signaling molecules/ions. We previously reported that both the phospholipid PIP2 itself and its hydrolysis to IP3 (Ca2+) stimulates the activity of NBCe1 expressed in oocytes. In this preparation, activating a co‐expressed voltage‐sensitive phosphatase (VSP) that dephosphorylates PIP2 to PIP without stimulating IP3/Ca2+ signaling decreases NBCe1 activity. In the current study, we examined the effect of the PIP2‐lowering phosphatase, inositol polyphosphate 5‐phosphatase encoded by the oculocerebrorenal syndrome of Lowe gene (OCRL) on the activity of NBCe1 variants expressed in oocytes. Mutations and variants of OCRL lead to Dent disease type 2, as well as Lowe Syndrome, which is characterized by cataracts, intellectual disability, basal ganglia calcification, and proximal renal tubular acidosis (pRTA). Using the 2‐electrode voltage‐clamp technique, we found that oocytes co‐expressing human OCRL with NBCe1‐A (both HA tagged) displayed a characteristic NBC‐mediated, HCO3–‐induced outward current (INBC) that was 59% smaller than oocytes expressing NBCe1‐A. We also observed OCRL inhibition of HA‐tagged NBCe1‐B and ‐C. We obtained similar results after replacing the HA tag on NBCe1‐A with a FLAG tag. The OCRL‐induced decrease in INBC could be explained by a decrease in NBCe1 expression at the plasma membrane. Co‐expressing OCRL caused a 44% decrease in INBC and a parallel 33% decrease in FLAG‐tagged NBCe1‐A oocyte surface expression as determined by single‐oocyte chemiluminescence. Thus, a physiological phosphatase that lowers PIP2 can regulate the activity and/or expression of NBCe1. Altered activity/expression of NBCe1 caused by mutant OCRL variants seen in Dent disease and Lowe Syndrome may contribute to observed patient symptoms, especially pRTA.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Anesthetic challenges in a child with Lowe's and Fanconi syndrome.

Oculocerebrorenal syndrome of Lowe is a rare X-linked metabolic disorder complicated by Fanconi's syndrome. Anaesthetic management of Lowe syndrome with Fanconi's syndrome is challenging to the anaesthesiologists in view of difficult airway due to microcephaly, metabolic abnormalities, and risk of peri-operative seizures. We report a successful anaesthetic management of a case of 2-year-old child scheduled for evaluation under anaesthesia following bilateral lens aspiration surgery.

Anesthetic Management of An Adolescent With Lowe Syndrome During Posterior Spinal Fusion

Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare X-linked disorder that was first described in 1952. Associated end-organ involvement includes the eye, central nervous system (CNS), and the kidney with proximal renal tubular acidosis. Life expectancy is reduced to mid-adulthood as a result of renal disease, hypotonia, and an increased susceptibility to infections. Given the multi-system involvement, surgical intervention may be required to address the sequelae of the disease process. We present a 16-year-old boy with Lowe syndrome who required anesthetic care for posterior spinal fusion for the treatment of neuromuscular scoliosis. Previous reports of anesthetic care of these patients are reviewed, end-organ involvement is discussed, and options for anesthetic care are presented. J Med Cases. 2017;8(12):388-392 doi: https://doi.org/10.14740/jmc2949w

Results of treatment of low lumbar pain syndrome by radiofrequency denervation of the facet joints

Background. The high prevalence of degenerative-dystrophic spine injury and low effectiveness of spondyloarthritis therapy makes relevant the treatment of low lumbar pain syndrome caused mainly by spondyloarthritis by innovative minimally invasive method of high-frequency denervation of facet joints.Purposes. To determine the effectiveness of the radiofrequency denervation of facet joints, taking into account early and long-term results of treatment, to eliminate the pain syndrome in patients with lower lumbar pain syndrome with predominating spondyloarthritis.Materials and methods. The early and long-term results of treatment by the method of high-frequency denervation of facet joints were analyzed using 1RFG-1A/RFG-1B (produced by Radionics) in 136 patients (73 men and 63 women aged from 44 to 81 years) with lower lumbar pain syndrome with the leading clinical manifestation of arthrosis of the articular joints. The pain syndrome was assessed four times – in the preoperative and postoperative periods (during the week), 3 months and a year after treatment. The visual analogue scale (VAS) of pain and the Oswestry index of disability index were used. The control group consisted of 31 patients (15 women and 16 men aged from 42 to 83 years) with lower lumbar pain with spondyloarthrosis dominating, which were treated non-operatively.Results. Immediately after treatment, a reliable result of treatment of chronic low-back pain syndrome in the basic and control groups with all structural and morphological changes of the spine was obtained both by the Oswestry disability scale and the visual analogue scale of pain (except the control group where spondyloarthritis was combined with large herniated discs, spinal stenosis, spondylolisthesis). Meanwhile there is clear and reliable difference between the basic group and the control group immediately after the treatment. After three months and a year after the treatment in both groups a reliable result was obtained only in the basic group, which indicates high efficiency of radiofrequency denervation of facet joints.Conclusions. Both early and long-term treatment results demonstrate efficacy and safety of high-frequency denervation of facet joints in patients with lower lumbar pain syndrome with spondyloarthrosis dominating. High-frequency denervation of facet joints should be included in the algorithm of treatment of facet syndrome in case of the ineffectiveness of drug treatment.

Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature.

The conditional use of actin during clathrin-mediated endocytosis in mammalian cells suggests that the cell controls whether and how actin is used. Using a combination of biochemical reconstitution and mammalian cell culture, we elucidate a mechanism by which the coincidence of PI(4,5)P2 and PI(3)P in a curved vesicle triggers actin polymerization. At clathrin-coated pits, PI(3)P is produced by the INPP4A hydrolysis of PI(3,4)P2, and this is necessary for actin-driven endocytosis. Both Cdc42⋅guanosine triphosphate and SNX9 activate N-WASP-WIP- and Arp2/3-mediated actin nucleation. Membrane curvature, PI(4,5)P2, and PI(3)P signals are needed for SNX9 assembly via its PX-BAR domain, whereas signaling through Cdc42 is activated by PI(4,5)P2 alone. INPP4A activity is stimulated by high membrane curvature and synergizes with SNX9 BAR domain binding in a process we call curvature cascade amplification. We show that the SNX9-driven actin comets that arise on human disease-associated oculocerebrorenal syndrome of Lowe (OCRL) deficiencies are reduced by inhibiting PI(3)P production, suggesting PI(3)P kinase inhibitors as a therapeutic strategy in Lowe syndrome.

PALLD Regulates Phagocytosis by Enabling Timely Actin Polymerization and Depolymerization.

PALLD is an actin cross-linker supporting cellular mechanical tension. However, its involvement in the regulation of phagocytosis, a cellular activity essential for innate immunity and physiological tissue turnover, is unclear. We report that PALLD is highly induced along with all-trans-retinoic acid-induced maturation of myeloid leukemia cells, to promote Ig- or complement-opsonized phagocytosis. PALLD mechanistically facilitates phagocytic receptor clustering by regulating actin polymerization and c-Src dynamic activation during particle binding and early phagosome formation. PALLD is also required at the nascent phagosome to recruit phosphatase oculocerebrorenal syndrome of Lowe, which regulates phosphatidylinositol-4,5-bisphosphate hydrolysis and actin depolymerization to complete phagosome closure. Collectively, our results show a new function for PALLD as a crucial regulator of the early phase of phagocytosis by elaborating dynamic actin polymerization and depolymerization.

РАННІ РЕЗУЛЬТАТИ ЛІКУВАННЯ ХВОРИХ ІЗ НИЖНЬОПОПЕРЕКОВИМ БОЛЬОВИМ СИНДРОМОМ, ДЕ ДОМІНУВАЛИ ПРОЯВИ СПОНДИЛОАРТРОЗУ З ВИКОРИСТАННЯМ РАДІОЧАСТОТНОЇ ДЕНЕРВАЦІЇ ФАСЕТКОВИХ СУГЛОБІВ У ПОЄДНАННІ З ПЕРИАРТИКУЛЯРНИМ ВВЕДЕННЯМ МІСЦЕВИХ АНЕСТЕТИКІВ ТА СТЕРОЇДНИХ ПРЕПАРАТІВ

Висока частота розповсюдженості дегенеративно-дистрофічного ураження хребта при малій ефективності терапії спондилоартрозу робить актуальним дослідження стосовно лікування нижньопоперекового болю, зумовленого переважно спондилоартрозом, інноваційним міні-інвазійним методом високочастотної денервації фасеткових суглобів у поєднанні з періартикулярним введенням місцевих анестетиків та стероїдних препаратів.Мета дослідження – визначити ефективність впливу радіочастотної денервації фасеткових суглобів у поєднанні з періартикулярним введенням місцевих анестетиків та стероїдних препаратів на ліквідацію больового синдрому у хворих із нижньопоперековим больовим синдромом, в яких переважали явища спондилоартрозу.Матеріали і методи. Проведено аналіз ранніх результатів лікування 78 пацієнтів (37 чоловіків та 41 жінки у віці від 51 до 79 років) з нижньопоперековим больовим синдромом, у яких ведучим клінічним проявом був артроз дуговідросткових суглобів, що склали основну групу, а також радіочастотну денервацію фасеткових суглобів (за допомогою апарату RFG-1A/RFG-1B фірми Radionics) в поєднанні з періартикулярним введенням місцевого анестетика та стероїдного препарату. Контрольну групу склали 136 пацієнтів (73 чоловіків та 63 жінки у віці від 44 до 81 років) із нижньопоперековим болем, де домінували явища спондилоартрозу, які лікувались виключно за допомогою методу радіочастотної денервації фасеткових суглобів.Результати досліджень та їх обговорення. Як відразу ж після проведеного лікування, так і через три місяці отримано достовірний результат лікування хронічного нижньопоперекового больового синдрому, зумовленого переважно ураженням дуговідросткових суглобів як в основній, так і контрольній групах, що свідчить про ефективність обох методів лікування. Разом з тим, є чітка достовірна різниця між основною та контрольною групами як відразу після проведеного лікування, так і через три місяці, що свідчить про достовірну вищу ефективність методу радіочастотної денервації фасеткових суглобів у поєднанні з періартикулярним введенням місцевого анестетика та стероїдного препарату в ранньому післяопераційному періоді.Висновки. Отримані результати як відразу ж після лікування, так і через 3 місяці свідчать як про ефективність радіочастотної денервації фасеткових суглобів, так і про ефективність радіочастотної денервації фасеткових суглобів у поєднанні з періартикулярним введенням місцевого анестетика та стероїдного препарату у хворих із нижньопоперековим больовим синдромом, де домінують явища спондилоартрозу. Достовірно кращі результати лікування отримані в ранньому післяопераційному періоді в групі пацієнтів, яким проводили радіочастотну денервацію фасеткових суглобів у поєднанні з періартикулярним введенням місцевого анестетика та стероїдного препарату.

A comparison of splicing assays to detect an intronic variant of the OCRL gene in Lowe syndrome

Lowe syndrome is an X-linked inherited disorder diagnosed by congenital cataracts, intellectual impairment, and renal tubular dysfunction. It is caused by pathogenic variants of the oculocerebrorenal syndrome of Lowe gene (OCRL), of which more than 250 have been reported so far. Around 30 of these variants are intronic nucleotide changes; however, to show the pathogenicity of these variants is usually laborious.In this report, we conducted genetic testing of a patient clinically diagnosed with Lowe syndrome to detect the presence of OCRL variants. We analyzed variant transcript expression in peripheral blood leukocytes and using a minigene construct in addition to in silico analysis.We detected a 9 base pair intronic insertion between OCRL exon 10 and exon 11 derived from the alteration of the splicing acceptor site in intron 10 caused by the intronic splicing variant NM_000276.3: c.940-11G>A (p.Lys313_Val314insAsnSer*). The findings obtained from transcript analysis of peripheral blood leukocytes and the minigene construct assay were identical to those of in silico analysis.All assays detected the same transcript abnormality and were reliable in revealing the pathogenicity of the intronic variant. The in vitro assay can also be used to clarify the complicated splicing mechanisms in inherited kidney diseases.

Finding patients using similarity measures in a rare diseases-oriented clinical data warehouse: Dr. Warehouse and the needle in the needle stack

ObjectiveIn the context of rare diseases, it may be helpful to detect patients with similar medical histories, diagnoses and outcomes from a large number of cases with automated methods. To reduce the time to find new cases, we developed a method to find similar patients given an index case leveraging data from the electronic health records. Materials and methodsWe used the clinical data warehouse of a children academic hospital in Paris, France (Necker-Enfants Malades), containing about 400,000 patients. Our model was based on a vector space model (VSM) to compute the similarity distance between an index patient and all the patients of the data warehouse. The dimensions of the VSM were built upon Unified Medical Language System concepts extracted from clinical narratives stored in the clinical data warehouse. The VSM was enhanced using three parameters: a pertinence score (TF-IDF of the concepts), the polarity of the concept (negated/not negated) and the minimum number of concepts in common. We evaluated this model by displaying the most similar patients for five different rare diseases: Lowe Syndrome (LOWE), Dystrophic Epidermolysis Bullosa (DEB), Activated PI3K delta Syndrome (APDS), Rett Syndrome (RETT) and Dowling Meara (EBS-DM), from the clinical data warehouse representing 18, 103, 21, 84 and 7 patients respectively. ResultsThe percentages of index patients returning at least one true positive similar patient in the Top30 similar patients were 94% for LOWE, 97% for DEB, 86% for APDS, 71% for EBS-DM and 99% for RETT. The mean number of patients with the exact same genetic diseases among the 30 returned patients was 51%. ConclusionThis tool offers new perspectives in a translational context to identify patients for genetic research. Moreover, when new molecular bases are discovered, our strategy will help to identify additional eligible patients for genetic screening.

Ocular Pathology of Oculocerebrorenal Syndrome of Lowe: Novel Mutations and Genotype-Phenotype Analysis

Mutations in the OCRL1 gene result in the oculocerebrorenal syndrome of Lowe, with symptoms including congenital bilateral cataracts, glaucoma, renal failure, and neurological impairments. OCRL1 encodes an inositol polyphosphate 5-phosphatase which preferentially dephosphorylates phosphatidylinositide 4,5 bisphosphate (PI(4,5)P2). We have identified two novel mutations in two unrelated Lowe syndrome patients with congenital glaucoma. Novel deletion mutations are detected at c.739-742delAAAG in Lowe patient 1 and c.1595-1631del in Lowe patient 2. End stage glaucoma in patient 2 resulted in the enucleation of the eye, which on histology demonstrated corneal keloid, fibrous infiltration of the angle, ectropion uvea, retinal gliosis, and retinal ganglion cell loss. We measured OCRL protein levels in patient keratinocytes and found that Lowe 1 patient cells had significantly reduced OCRL protein as compared to the control keratinocytes. Genotype-phenotype correlation of OCRL1 mutations associated with congenital glaucoma revealed clustering of missense and deletion mutations in the 5-phosphatase domain and the RhoGAP-like domain. In conclusion, we report novel OCRL1 mutations in Lowe syndrome patients and the corresponding histopathologic analysis of one patient’s ocular pathology.

Gonadotrophin abnormalities in an infant with Lowe syndrome.

SummaryThis case, presenting with bilateral impalpable testes, illustrates the relevance of a broad differential disorders of sex development case management. It provides new insights on hypothalamic–pituitary–gonadal (HPG) axis and testicular function abnormalities in the multisystem disorder of Lowe syndrome. Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare disorder characterised by eye abnormalities, central nervous system involvement and proximal renal tubular acidosis. There are a handful of reports of pubertal delay, infertility and cryptorchidism in Lowe syndrome. Biochemistry aged 72 h: testosterone 6.4 nmol/L, LH <0.5 IU/L and FSH <0.5 IU/L. Gonadotropin-releasing hormone stimulation test identified significantly raised baseline LH = 45.4 IU/L (contrasts with earlier undetectable LH), with a 20% increase on stimulation, while baseline FSH = 4.3 IU/L with no increase on stimulation. Day 14 HCG stimulation test produced an acceptable 50% increase in testosterone. The constellation of further abnormalities suggested Lowe syndrome: hypotonia, bilateral cataracts (surgical extraction and intraocular lens implantation) and renal tubular acidosis (microscopic haematuria, hypercalciuria, proteinuria, generalised aminoaciduria, hypophosphataemia and metabolic acidosis). DNA sequencing identified de novo hemizygous frameshift mutation OCRL c.2409_2410delCT in exon 22. Interpretation of initial and repeat GnRH and HCG testing indicates the likelihood of testicular failure. Partial testicular descent occurred but left orchidopexy was required. Improving long-term gonadal function in Lowe syndrome assumes increased importance for current cohorts as advances in renal replacement therapy have greatly improved life expectancy. Noting HPG axis abnormalities in Lowe syndrome in infancy can identify cases requiring increased surveillance of pubertal progress for earlier detection and management.Learning points:Clinical endocrine problems in Lowe syndrome has been reported, but has focused on abnormalities in adolescence and young adulthood: pubertal delay and infertility.We present an infant with isolated LH elevation at baseline and on GnRH stimulation testing who also had bilateral impalpable testes.Early testing of the HPG axis in patients with Lowe syndrome may help predict gonadal abnormalities from a younger age, which will enhance the overall case management into adolescence.

Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome.

Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, mental retardation, and proximal renal tubular dysfunction. Mutations in OCRL, an inositol polyphosphate 5-phosphatase that dephosphorylates PI(4,5)P2, cause Lowe syndrome. Previously we showed that OCRL localizes to the primary cilium, which has a distinct membrane phospholipid composition, but disruption of phosphoinositides in the ciliary membrane is poorly understood. Here, we demonstrate that cilia from Lowe syndrome patient fibroblasts exhibit increased levels of PI(4,5)P2 and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P2 build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P2 was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in Ocrl-null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wild-type OCRL reversed the elevated PI(4,5)P2 in Lowe patient cells. Accumulation of sonic hedgehog protein in response to hedgehog agonist was decreased in MEFs derived from a Lowe syndrome mouse model. Together, our findings show for the first time an abnormality in ciliary phosphoinositides of both human and mouse cell models of Lowe syndrome.

Anesthetic Management of An Adolescent With Lowe Syndrome During Posterior Spinal Fusion

Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare X-linked disorder that was first described in 1952. Associated end-organ involvement includes the eye, central nervous system (CNS), and the kidney with proximal renal tubular acidosis. Life expectancy is reduced to mid-adulthood as a result of renal disease, hypotonia, and an increased susceptibility to infections. Given the multi-system involvement, surgical intervention may be required to address the sequelae of the disease process. We present a 16-year-old boy with Lowe syndrome who required anesthetic care for posterior spinal fusion for the treatment of neuromuscular scoliosis. Previous reports of anesthetic care of these patients are reviewed, end-organ involvement is discussed, and options for anesthetic care are presented. J Med Cases. 2017;8(12):388-392 doi: https://doi.org/10.14740/jmc2949w

Infrared Thermographic Pattern of Lower Limb Complex Regional Pain Syndrome (Type I) and its Correlation with Pain, Disease Duration and Clinical Signs

Purpose: So far, the use of infrared-thermography in the diagnosis of the Complex Regional Pain Syndrome (CRPS) has been described only for the upper extremity or jointly for the upper and lower extremity. Therefore, the aim of this study was the assessment of the absolute temperature side-to-side difference by infrared thermography in patients with CRPS Type I of the lower limb. It was investigated whether there are correlations between the amount of temperature side-to-side difference, pain, duration of the disease and clinical signs. Materials and Methods: 25 women and 11 men (mean age 48 years), who fulfilled the Budapest clinical criteria of CRPS type I, were investigated in this retrospective cross-sectional study. Infrared thermographic evaluation of the big toe, dorsal foot, ankle and distal anterior lower thigh was performed. The arithmetical mean of the absolute side-to-side differences of these 4 regions of interest was calculated=average side-to-side temperature difference of the distal lower limb. The correlation of the average side-to-side temperature difference of the distal lower limb with pain, duration of the disease and clinical signs (sensory, vasomotor, sudomotor/edema and motor/trophic) was assessed. Results: The average absolute side-to-side temperature difference of the distal lower limb was 1.6/1.2°C (mean/SD). A significant correlation between the temperature asymmetry was observed with the vasomotor signs. Conclusions: Infrared thermography offers an objective assessment of vasomotoric dysfunction in CRPS type I of the lower limb, and therefore serves as a useful supplementary tool in the diagnosis of CRPS type I.

Kidney Tubular Ablation of Ocrl/Inpp5b Phenocopies Lowe Syndrome Tubulopathy.

Lowe syndrome and Dent disease are two conditions that result from mutations of the inositol 5-phosphatase oculocerebrorenal syndrome of Lowe (OCRL) and share the feature of impaired kidney proximal tubule function. Genetic ablation of Ocrl in mice failed to recapitulate the human phenotypes, possibly because of the redundant functions of OCRL and its paralog type 2 inositol polyphosphate-5-phosphatase (INPP5B). Germline knockout of both paralogs in mice results in early embryonic lethality. We report that kidney tubule-specific inactivation of Inpp5b on a global Ocrl-knockout mouse background resulted in low molecular weight proteinuria, phosphaturia, and acidemia. At the cellular level, we observed a striking impairment of clathrin-dependent and -independent endocytosis in proximal tubules, phenocopying what has been reported for Dent disease caused by mutations in the gene encoding endosomal proton-chloride exchange transporter 5. These results suggest that the functions of OCRL/INPP5B and proton-chloride exchange transporter 5 converge on shared mechanisms, the impairment of which has a dramatic effect on proximal tubule endocytosis.

Exome-first approach identified a novel gloss deletion associated with Lowe syndrome

Lowe syndrome (LS) is an X-linked disorder affecting the eyes, nervous system and kidneys, typically caused by missense or nonsense/frameshift OCRL mutations. We report a 6-month-old male clinically suspected to have LS, but without the Fanconi-type renal dysfunction. Using a targeted-exome sequencing-first approach, LS was diagnosed by the identification of a deletion involving 1.7 Mb at Xq25-q26.1, encompassing the entire OCRL gene and neighboring loci.