Low Syndrome Research Articles

Lax lower extremity pain syndrome

Lax lower extremity pain syndrome

The Lowe syndrome protein OCRL1 is involved in primary cilia assembly

Lowe syndrome (LS) is a devastating, X-linked genetic disease characterized by the presence of congenital cataracts, profound learning disabilities and renal dysfunction. Unfortunately, children affected with LS often die early of health complications including renal failure. Although this syndrome was first described in the early 1950s and the affected gene, OCRL1, was identified more than 17 years ago, the mechanism by which Ocrl1 defects lead to LS's symptoms remains unknown. Here we show that LS display characteristics of a ciliopathy. Specifically, we found that patients' cells have defects in the assembly of primary cilia and this phenotype was reproduced in cell lines by knock-down of Ocrl1. Importantly, this defect could be rescued by re-introduction of WT Ocrl1 in both patient and Ocrl1 knock-down cells. In addition, a zebrafish animal model of LS exhibited cilia defects and multiple morphological and anatomical abnormalities typically seen in ciliopathies. Mechanistically, we show that Ocrl1 is involved in protein trafficking to the primary cilia in an Rab8-and IPIP27/Ses-dependent manner. Taking into consideration the relevance of the signaling pathways hosted by the primary cilium, our results suggest hitherto unrecognized mechanisms by which Ocrl1 deficiency may contribute to the phenotypic characteristics of LS. This conceptual change in our understanding of the disease etiology may provide an alternative avenue for the development of therapies.

Lowe syndrome

Lowe syndrome (LS) is a lethal X-linked genetic disease caused by functional deficiencies of the phosphatidlyinositol 5-phosphatase, Ocrl1. In the past four years, our lab described the first Ocrl1-specific cellular phenotypes using dermal fibroblasts from LS patients. These phenotypes, validated in an ocrl1-morphant zebrafish model, included membrane remodeling (cell migration/spreading, fluid-phase uptake) defects and primary cilia assembly abnormalities. On one hand, our findings unraveled cellular phenotypes likely to be involved in the observed developmental defects; on the other hand, these discoveries established LS as a ciliopathy-associated disease. This article discusses the possible mechanisms by which loss of Ocrl1 function may affect RhoGTPase signaling pathways leading to actin cytoskeleton rearrangements that underlie the observed cellular phenotypes.

Phosphatidylinositol 4-Kinases and PI4P Metabolism in the Nervous System: Roles in Psychiatric and Neurological Diseases

The four mammalian phosphatidylinositol 4-kinases, together with the PI(4,5)P(2) depleting 5-phosphatases of the oculocerebrorenal syndrome of Lowe and synaptojanin families, modulate neuronal pools of PI4P lipid and regulate intracellular membrane trafficking in the endocytic and secretory pathways. Dysfunctions in these enzymes have been associated with a broad spectrum of disorders including schizophrenia, bipolar disorder, Lowe syndrome, age-related neurodegeneration, Alzheimer's disease and Down syndrome. Recent work has shown that reduced expression of individual phosphatidylinositol 4-kinase isozymes is associated with impaired survival of specific neuronal populations within the CNS. Furthermore, alterations to the concentrations of different phosphoinositide lipid species in the brain and, in particular, the ratio of PI4P to PI(4,5)P(2) can have deleterious effects on clathrin-dependent membrane trafficking both in the Golgi-endosomal pathway and at the plasma membrane. In this article, we focus on the cell biology, biochemistry and neuronal functions of the phosphatidylinositol 4-kinases and their emerging roles in psychiatric and neurological pathologies.

A Premature Termination Mutation in a Patient with Lowe Syndrome without Congenital Cataracts: Dropping the “O” in OCRL

The oculocerebrorenal syndrome of Lowe is an X-linked recessive disorder characterized by the triad of congenital cataracts, mental retardation and a renal proximal tubulopathy. Although severity of phenotype might vary, congenital cataracts are part of the definition of this rare disorder.We report a 13-year-old patient with the typical cerebrorenal phenotype of Lowe syndrome, that had remained undiagnosed due to absence of any ocular involvement. OCRL gene analysis was carried.DNA analysis revealed a c.C760T (p.Gln199X) nonsense mutation in exon 8 expected to cause complete disruption of OCRL function. After sequencing the parents of the index patient and his maternal grandparents, this mutation turned out to be de novo in the mother. Furthermore, a silent variant (p.Arg35=) was identified in exon 2, that could also be identified in the mother and her 3 sisters, but not in the grandparents assuming germ cell mosaicism in either of the grandparents. RNA analysis from the patient's lymphocytes revealed presence of full-length OCRL transcripts. Western blotting from lymphocyte samples failed to detect OCRL protein even in controls.Our findings extend the phenotypic spectrum caused by OCRL mutations and illustrate that there may be selective organ involvement in Lowe syndrome.

The 5-phosphatase OCRL mediates retrograde transport of the mannose 6-phosphate receptor by regulating a Rac1-cofilin signalling module

Mutations in the OCRL gene encoding the phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) 5-phosphatase OCRL cause Lowe syndrome (LS), which is characterized by intellectual disability, cataracts and selective proximal tubulopathy. OCRL localizes membrane-bound compartments and is implicated in intracellular transport. Comprehensive analysis of clathrin-mediated endocytosis in fibroblasts of patients with LS did not reveal any difference in trafficking of epidermal growth factor, low density lipoprotein or transferrin, compared with normal fibroblasts. However, LS fibroblasts displayed reduced mannose 6-phosphate receptor (MPR)-mediated re-uptake of the lysosomal enzyme arylsulfatase B. In addition, endosome-to-trans Golgi network (TGN) transport of MPRs was decreased significantly, leading to higher levels of cell surface MPRs and their enrichment in enlarged, retromer-positive endosomes in OCRL-depleted HeLa cells. In line with the higher steady-state concentration of MPRs in the endosomal compartment in equilibrium with the cell surface, anterograde transport of the lysosomal enzyme, cathepsin D was impaired. Wild-type OCRL counteracted accumulation of MPR in endosomes in an activity-dependent manner, suggesting that PI(4,5)P(2) modulates the activity state of proteins regulated by this phosphoinositide. Indeed, we detected an increased amount of the inactive, phosphorylated form of cofilin and lower levels of the active form of PAK3 upon OCRL depletion. Levels of active Rac1 and RhoA were reduced or enhanced, respectively. Overexpression of Rac1 rescued both enhanced levels of phosphorylated cofilin and MPR accumulation in enlarged endosomes. Our data suggest that PI(4,5)P(2) dephosphorylation through OCRL regulates a Rac1-cofilin signalling cascade implicated in MPR trafficking from endosomes to the TGN.

A novel and de novo deletion in the OCRL1 gene associated with a severe form of Lowe syndrome

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder. The mutation of the gene OCRL1 localized at Xq26.1, coding for the enzyme phosphatidylinositol (4,5) bisphosphate (PIP2P) 5-phosphatase, is responsible for the phenotypic characteristics of the disease. We report a 22-year-old male with a severe form of OCRL syndrome, diagnosed on the basis of congenital cataracts, severe psychomotor and cognitive deficits, and renal tubular dysfunction without Fanconi syndrome. The patient presented low molecular weight proteinuria, nephrocalcinosis, nephrolithiasis, rickets, and growth retardation and developed progressive renal failure. Genetic analysis showed a novel and de novo deletion of exons 10-13 in the OCRL1 gene.

OCRL1Modulates Cilia Length in Renal Epithelial Cells

Lowe syndrome is an X-linked disorder characterized by cataracts at birth, mental retardation and progressive renal malfunction that results from loss of function of the OCRL1 (oculocerebrorenal syndrome of Lowe) protein. OCRL1 is a lipid phosphatase that converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate. The renal pathogenesis of Lowe syndrome patients has been suggested to result from alterations in membrane trafficking, but this cannot fully explain the disease progression. We found that knockdown of OCRL1 in zebrafish caused developmental defects consistent with disruption of ciliary function, including body axis curvature, pericardial edema, hydrocephaly and impaired renal clearance. In addition, cilia in the proximal tubule of the zebrafish pronephric kidney were longer in ocrl morphant embryos. We also found that knockdown of OCRL1 in polarized renal epithelial cells caused elongation of the primary cilium and disrupted formation of cysts in three-dimensional cultures. Calcium release in response to ATP was blunted in OCRL1 knockdown cells, suggesting changes in signaling that could lead to altered cell function. Our results suggest a new role for OCRL1 in renal epithelial cell function that could contribute to the pathogenesis of Lowe syndrome.

Lowe syndrome 환아의 치과적 치료 : 증례보고

Lowe syndrome은 X-염색체 반성열성 유전 질환으로 1952년 Lowe 등에 의해 처음으로 보고되었다. 대부분 남성에게 발생하며, 주요 임상증상으로는 선천성 백내장 및 녹내장 등의 안구증상, 정신지체 및 근긴장저하 등의 근신경계 증상, 신장의 기능이상 등이 있고, 정신지체에 의한 행동조절 문제로 인해 전신마취를 시행할 경우 신장 기능 저하에 따른 대사성 산증과 악성 고열 발생의 위험성이 높아진다. Lowe syndrome으로 진단된 10세 2개월 된 남아가 치석이 많고, 칫솔질이 어렵다는 것을 주소로 전남대학교 치과병원 소아치과에 내원하였다. 임상 검사 시 전반적으로 심한 치석의 침착, 법랑질 형성 부전, 변연성 치은염, 영구치의 맹출 지연, 전반적인 치아 동요 등의 소견을 보였으며, 심한 정신지체로 인해 환자의 협조도가 부족하여 진정요법 하에 외래에서 치과치료를 시행하였다. 행동조절의 어려움과 전신마취시의 위험성, 대사장애 처치에 사용되는 각종 약물로 인한 치아착색과 치석형성의 용이함 때문에 Lowe syndrome 환아의 치과적 관리는 특히 예방에 중점을 두어야 한다. Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare genetic disorder involving eyes, kidney, brain and musculoskeletal system, and occurs predominantly in males. The patient with Lowe syndrome is characterized with congenital cataracts, glaucoma, prominent forehead, thin and sparse hair, mental and growth retardation, muscular hypotonia, renal dysfunction, and metabolic bone disease. We have experienced a 10-year-old boy with Lowe syndrome who had poor oral hygiene and trouble for teeth brushing. To manage his behavior and systemic metabolic disorder, sedation was performed during dental care. Excessive calculus formation in this patient is caused by both medication and lack of ability to maintain oral hygiene. The dental management of those patients has to be focused on prevention due to difficulties in dental treatment and dangers of general anesthesia for the Lowe syndrome.

Phosphatidylinositol 5-Phosphatase Oculocerebrorenal Syndrome of Lowe Protein (OCRL) Controls Actin Dynamics during Early Steps of Listeria monocytogenes Infection

Listeria monocytogenes is a bacterial pathogen that induces its own entry into a broad range of mammalian cells through interaction of the bacterial surface protein InlB with the cellular receptor Met, promoting an actin polymerization/depolymerization process that leads to pathogen engulfment. Phosphatidylinositol bisphosphate (PI[4,5]P(2)) and trisphosphate (PI[3,4,5]P(3)) are two major phosphoinositide species that function as molecular scaffolds, recruiting cellular effectors that regulate actin dynamics during L. monocytogenes infection. Because the phosphatidylinositol 5'-phosphatase OCRL dephosphorylates PI(4,5)P(2) and to a lesser extent PI(3,4,5)P(3), we investigated whether this phosphatase modulates cell invasion by L. monocytogenes. Inactivation of OCRL by small interfering RNA (siRNA) leads to an increase in the internalization levels of L. monocytogenes in HeLa cells. Interestingly, OCRL depletion does not increase but rather decreases the surface expression of the receptor Met, suggesting that OCRL controls bacterial internalization by modulating signaling cascades downstream of Met. Immuno-fluorescence microscopy reveals that endogenous and overexpressed OCRL are present at L. monocytogenes invasion foci; live-cell imaging additionally shows that actin depolymerization coincides with EGFP-OCRL-a accumulation around invading bacteria. Together, these observations suggest that OCRL promotes actin depolymerization during L. monocytogenes infection; in agreement with this hypothesis, OCRL depletion leads to an increase in actin, PI(4,5)P(2), and PI(3,4,5)P(3) levels at bacterial internalization foci. Furthermore, in cells knocked down for OCRL, transfection of enzymatically active EGFP-OCRL-a (but not of a phosphatase-dead enzyme) decreases the levels of intracellular L. monocytogenes and of actin associated with invading bacteria. These results demonstrate that through its phosphatase activity, OCRL restricts L. monocytogenes invasion by modulating actin dynamics at bacterial internalization sites.

Abstract P074: Substituting Homemade Fruit Juice for Sugar-Sweetened Beverages is Associated with Lower Odds of Metabolic Syndrome among Hispanic Adults

Introduction: Consumption of sugar sweetened beverages (SSB) has been consistently associated with metabolic syndrome (MetS), while results on the role of fruit juice intake are conflicting. Hispanics consume both SSB and traditional fruit-based beverages; however, studies conducted on such ethnic group are scarce. Given the high prevalence of MetS among Hispanics, describing putative contributors to this condition is essential in proposing approaches that may successfully reduce its prevalence and avoid further complications. Hypothesis: We assessed the hypothesis that substituting fruit-based beverages traditionally consumed by Hispanics for SSB may be associated with lower odds of MetS. Methods: To determine the cross-sectional association between beverages consumed by Hispanics, and MetS and its components, data were analyzed in 1,872 Costa Rican adults who served as controls of a population-based case-control study of coronary heart disease. Multivariate adjusted means were calculated for components of MetS by servings (never, <1/week, 2–6/week, ≥1/day) of two traditional fruit-based beverages (‘fresco’ and homemade fruit juice, separately) and two SSB (instant drinks and regular sodas, separately and combined). Prevalence ratio (PR) of MetS was calculated for each beverage, and odds ratio (OR) was calculated by substituting one serving of homemade fruit juice or water for one of SSB. Results: Significant positive trends were observed for increasing servings of instant drinks and combined SSB with plasma triglyceride and waist circumference, and for regular soda with waist circumference (all P -trend<0.001). Increasing servings of homemade fruit juice were associated positively with HDL-C ( P -trend=0.033). Consuming ≥1 serving/day of instant drinks was associated with higher PR of MetS (1.42, 95%CI: 1.11, 1.83) compared to no consumption; similar results were obtained for combined SSB. Substituting one serving of homemade fruit juice for instant drink was associated with 29% (95% CI=7, 47%) lower odds of MetS, and for regular soda with 30% (1, 50%) lower odds. Substituting water for combined SSB was marginally significant (OR=0.86 (0.74, 1.00). Conclusion: In conclusion, reducing consumption of SSB and substituting them with homemade fruit juices in moderation, may be a culturally-appropriate approach to lower metabolic syndrome among Hispanics. Our study provides the groundwork for interventions on beverage intake that aim to prevent MetS and type 2 diabetes in Hispanic ethnic subgroups, and may support current public health efforts on limiting availability and intake of SSB, while substituting with a healthy beverage.

Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease

Oculocerebrorenal syndrome of Lowe (OCRL) gene product is a phosphatidyl inositol 4,5-bisphosphate [PI(4,5)P(2)] 5-phosphatase, and mutations of OCRL cause Lowe syndrome and Dent disease, both of which are frequently associated with hypercalciuria. Transient receptor potential, vanilloid subfamily, subtype 6 (TRPV6) is an intestinal epithelial Ca(2+) channel mediating active Ca(2+) absorption. Hyperabsorption of Ca(2+) was found in patients of Dent disease with increased Ca(2+) excretion. In this study, we tested whether TRPV6 is regulated by OCRL and, if so, to what extent it is altered by Dent-causing OCRL mutations using Xenopus laevis oocyte expression system. Exogenous OCRL decreased TRPV6-mediated Ca(2+) uptake by regulating the function and trafficking of TRPV6 through different domains of OCRL. The PI(4,5)P(2) 5-phosphatase domain suppressed the TRPV6-mediated Ca(2+) transport likely through regulating the PI(4,5)P(2) level needed for TRPV6 function without affecting TRPV6 protein abundance of TRPV6 at the cell surface. The forward trafficking of TRPV6 was decreased by OCRL. The Rab binding domain in OCRL was involved in regulating the trafficking of TRPV6. Knocking down endogenous X. laevis OCRL by antisense approach increased TRPV6-mediated Ca(2+) transport and TRPV6 forward trafficking. All seven Dent-causing OCRL mutations examined exhibited alleviation of the inhibitory effect on TRPV6-mediated Ca(2+) transport together with decreased overall PI(4,5)P(2) 5-phosphatase activity. In conclusion, OCRL suppresses TRPV6 via two separate mechanisms. The disruption of PI(4,5)P(2) 5-phosphatase activity by Dent-causing mutations of OCRL may lead to increased intestinal Ca(2+) absorption and, in turn, hypercalciuria.

Adjuvant surgery in patients with testicular cancer undergoing post-chemotherapy retroperitoneal lymph node dissection.

335 Background: Up to 50% of patients who undergo induction chemotherapy for metastatic germ cell cancer have significant residual retroperitoneal disease in whom post chemotherapy RPLND is indicated with intent to cure. Since complete resection is a critical component in PC-RPLND, meticulous dissection of the retroperitoneum with resection of involved organs or structures (adjuvant surgery) should be considered whenever feasible to ensure optimal outcome. Methods: From 2004 to 2010, 85 testicular cancer patients underwent PC-RPLND by a single surgeon (SD). A bilateral template approach was utilized with nerve sparing technique whenever feasible. The clinico-pathologic and outcome of patients who underwent adjuvant surgery during PC-RPLND were reviewed. Results: Of 85 patients undergoing PC-RPLND, 28 (33%) required adjuvant procedures. Thirteen (15%) required vascular procedures including cavotomy/ caval resection in six, aortic resection in eight, common iliac vessels resection in four and renal vessels resection/reimplant in two. Twelve patients (14%) required adjuvant nephrectomy (10/12 left sided). There was 1 ureteral resection with appendiceal substitution, 1 partial duodenectomy, 2 cholecystectomy, 2 thoracotomies, 4 liver resection/ biopsy, and 1 neck dissection. There were 8 early complications (28%) including vocal cord paralysis, brachial plexus injury, lower extremities compartment syndrome, thigh numbness, UGI bleeding, retroperitoneal hematoma and alcohol withdrawal. No peri-operative death was reported. Retroperitoneal pathology revealed mature teratoma in 11 (39%), fibrosis in 8 (28%) and viable germ cell tumor (GCT) in 9 (32%) patients. 75%, 82% and 66% of patients with fibrosis, teratoma and viable GCT had no evidence of recurrence in mean follow up of 18 months. Conclusions: A significant number of patients undergoing PC-RPLND require adjuvant surgery including vascular procedures and nephrectomy. The excellent outcomes associated with low operative morbidity/mortality validate such aggressive surgical approaches performed by experienced surgeons.

The Lowe syndrome protein OCRL1 is involved in primary cilia assembly

Lowe syndrome (LS) is a devastating, X-linked genetic disease characterized by the presence of congenital cataracts, profound learning disabilities and renal dysfunction. Unfortunately, children affected with LS often die early of health complications including renal failure. Although this syndrome was first described in the early 1950s and the affected gene, OCRL1, was identified more than 17 years ago, the mechanism by which Ocrl1 defects lead to LS's symptoms remains unknown. Here we show that LS display characteristics of a ciliopathy. Specifically, we found that patients' cells have defects in the assembly of primary cilia and this phenotype was reproduced in cell lines by knock-down of Ocrl1. Importantly, this defect could be rescued by re-introduction of WT Ocrl1 in both patient and Ocrl1 knock-down cells. In addition, a zebrafish animal model of LS exhibited cilia defects and multiple morphological and anatomical abnormalities typically seen in ciliopathies. Mechanistically, we show that Ocrl1 is involved in protein trafficking to the primary cilia in an Rab8-and IPIP27/Ses-dependent manner. Taking into consideration the relevance of the signaling pathways hosted by the primary cilium, our results suggest hitherto unrecognized mechanisms by which Ocrl1 deficiency may contribute to the phenotypic characteristics of LS. This conceptual change in our understanding of the disease etiology may provide an alternative avenue for the development of therapies.

Systemic onset Juvenile Idiopathic Arthritis (SoJIA): a monocentric study of 114 patients

Results During the study period, 114 children were included. Mean age at diagnosis was 4 years and 4 months (range, 4 months to 15.5 years). Familial history of autoimmunity was found in 27% of the patients. Glycosylated ferritin was low (≤20%) for 79% of patients. Twelve percent of patients had macrophage activation syndrome, 2 patients anti-neutrophil cytoplasmic antibodies (ANCA) associated glomerulonephritis, 3 patients pulmonary restrictive syndrome without vertebral arthritis, and one patient Crohn’s disease; 11 % had positive antinuclear antibody (ANA) (≥1/160) at diagnosis. None developed neoplasia. Patients in whom diagnosis was made after 2000, and had been treated by biotherapy, especially anakinra, had less osteoarticular sequelae and lower inflammatory syndrome (p = 0,004) than others (Figure 1). Early polyarticular and wrists involvements were associated to a poor outcome (p = 0,009, p = 0,027).

Lower extremity complex regional pain syndrome type II after a craniotomy: case report

Complex regional pain syndrome (CRPS) is a collection of signs and symptoms that most often include regional pain, edema, changes in skin temperature, increased skin sensitivity, and weakness that usually affects the extremities. It almost always exclusively affects the surgical site. A 52 year old woman presented with lower extremity CRPS due to positioning after a craniotomy.

GnRH agonist protocol versus GnRH antagonist protocol in assisted reproduction

GnRH agonist protocol versus GnRH antagonist protocol in assisted reproduction

Actin regulation during abscission: unexpected roles of Rab35 and endocytic transport

Actin regulation during abscission: unexpected roles of Rab35 and endocytic transport

OCRL1 mutation in a boy with Dent disease, mild mental retardation, but without cataracts

Oculocerebrorenal (Lowe) syndrome is an X-linked multisystem disease characterized by renal proximal tubulopathy, mental retardation, and congenital cataracts. We present a 19-year-old boy who was found to have low molecular weight proteinuria, hypercalciuria, mild generalized hyperaminoaciduria and intermittent microscopic hematuria at the age of 3. Standard clinical and biochemical examinations and mutational analysis of the CLNC5 and OCRL1 gene were performed for the patient. The patient fulfilled diagnostic criteria for Dent disease, but lacked mutation in CLCN5. Sequencing of candidate genes revealed a mutation in his OCRL1 gene, which encodes for enzyme PIP2 5-phosphatase. The enzyme was not detected by western blot analysis, and decreased activity of the enzyme PIP2 5-phosphatase was observed in cultured skin fibroblasts. The boy had only mild mental retardation, mildly elevated muscle enzymes, but no neurological deficit or congenital cataracts, which are typical for Lowe syndrome. Children with Dent phenotype who lack CLCN5 mutation should be tested for OCRL1 mutation. OCRL1 mutations may present with mild clinical features and are not necessarily associated with congenital cataracts.

Contrast-Enhanced Ultrasound in the Early Diagnosis of Acute Lower Leg Compartment Syndrome

Contrast-Enhanced Ultrasound in the Early Diagnosis of Acute Lower Leg Compartment Syndrome