Low Syndrome Research Articles

Index of Suspicion

Index of Suspicion

Bilateral Lower Limb Compartment Syndrome following Radical Cystectomy and Urinary Diversion in the Supine Position

Bilateral Lower Limb Compartment Syndrome following Radical Cystectomy and Urinary Diversion in the Supine Position

Amelioration of Hypophosphatemic Rickets and Osteoporosis With Pamidronate and Growth Hormone in Lowe Syndrome

The oculocerebrorenal syndrome of Lowe, an X-linked multisystem disorder, was diagnosed in a male patient who presented with typical abnormalities of the eyes, kidneys and nervous system. Besides congenital cataracts, renal tubular dysfunction and psychomotor retardation, the patient had also suffered from profound failure to thrive, growth hormone deficiency, severe osteoporosis with hypophosphatemic rickets, and progressive renal dysfunction since early childhood, which were attributed to the metabolic derangements following Fanconi syndrome. Direct sequencing of the OCRL1 gene (responsible for the oculocerebrorenal syndrome of Lowe) revealed a de novo c.2282_2283insT in exon 20, which resulted in premature termination of translation (D762X). After monthly intravenous administration of pamidronate since the age of 17.8 years, his urine creatinine clearance and tubular resorption of phosphate increased slightly and bone mineral density was much improved (Z score increased from -7.3 to -3.3) without deterioration of renal function. Simultaneous growth hormone therapy enhanced the positive response. The beneficial osseous and renal effects of the bisphosphonate, along with growth hormone treatment in Lowe syndrome with hypophosphatemia, may be related to reduced renal calcium and phosphate excretion.

Inherited cerebrorenal syndromes

Abnormalities in the central nervous system and renal function are seen together in a variety of congenital syndromes. This Review examines the clinical presentation and the genetic basis of several such syndromes. The X-linked oculocerebrorenal syndrome of Lowe is characterized by developmental delay, blindness, renal tubular dysfunction, and progressive renal failure. This syndrome results from mutations in the OCRL gene, which encodes a phosphatase involved in endosomal trafficking. Mutations in OCRL also occur in Dent disease, which has a milder disease phenotype than Lowe syndrome. Patients with Joubert syndrome have cerebellar ataxia, pigmentary retinopathy, and nephronophthisis. Joubert syndrome is a genetically heterogeneous condition associated with mutations in at least five genes that encode ciliary proteins. Bardet-Biedl syndrome is a clinically variable condition associated with learning disabilities, progressive visual loss, obesity, polydactyly, hypogonadism, and cystic and fibrotic renal changes that can lead to renal failure. Most of the 12 genes mutated in Bardet-Biedl syndrome are also involved in ciliary function, as are the genes implicated in other 'ciliopathies' with similar phenotypes, including Meckel syndrome.

Lowe syndrome patient fibroblasts display Ocrl1-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase

The Lowe syndrome (LS) is a life-threatening, developmental disease characterized by mental retardation, cataracts and renal failure. Although this human illness has been linked to defective function of the phosphatidylinositol 5-phosphatase, Ocrl1 (Oculo-Cerebro-Renal syndrome ofLowe protein1), the mechanism by which this enzyme deficiency triggers the disease is not clear. Ocrl1 is known to localize mainly to the Golgi apparatus and endosomes, however it translocates to plasma membrane ruffles upon cell stimulation with growth factors. The functional implications of this inducible translocation to the plasma membrane are presently unknown. Here we show that Ocrl1 is required for proper cell migration, spreading and fluid-phase uptake in both established cell lines and human dermal fibroblasts. We found that primary fibroblasts from two patients diagnosed with LS displayed defects in these cellular processes. Importantly, these abnormalities were suppressed by expressing wild-type Ocrl1 but not by a phosphatase-deficient mutant. Interestingly, the homologous human PI-5-phosphatase, Inpp5b, was unable to complement the Ocrl1-dependent cell migration defect. Further, Ocrl1 variants that cannot bind the endocytic adaptor AP2 or clathrin, like Inpp5b, were less apt to rescue the migration phenotype. However, no defect in membrane recruitment of AP2/clathrin or in transferrin endocytosis by patient cells was detected. Collectively, our results suggest that Ocrl1, but not Inpp5b, is involved in ruffle-mediated membrane remodeling. Our results provide new elements for understanding how Ocrl1 deficiency leads to the abnormalities associated with the LS.

Sensory-Motor Cortical Rorganization in Lower Motor Neuron Syndrome

Sensory-Motor Cortical Rorganization in Lower Motor Neuron Syndrome

A PH domain within OCRL bridges clathrin-mediated membrane trafficking to phosphoinositide metabolism

OCRL, whose mutations are responsible for Lowe syndrome and Dent disease, and INPP5B are two similar proteins comprising a central inositol 5-phosphatase domain followed by an ASH and a RhoGAP-like domain. Their divergent NH2-terminal portions remain uncharacterized. We show that the NH2-terminal region of OCRL, but not of INPP5B, binds clathrin heavy chain. OCRL, which in contrast to INPP5B visits late stage endocytic clathrin-coated pits, was earlier shown to contain another binding site for clathrin in its COOH-terminal region. NMR structure determination further reveals that despite their primary sequence dissimilarity, the NH2-terminal portions of both OCRL and INPP5B contain a PH domain. The novel clathrin-binding site in OCRL maps to an unusual clathrin-box motif located in a loop of the PH domain, whose mutations reduce recruitment efficiency of OCRL to coated pits. These findings suggest an evolutionary pressure for a specialized function of OCRL in bridging phosphoinositide metabolism to clathrin-dependent membrane trafficking.

MOTOR NEURON DISEASE FEATURES IN A PATIENT WITH NEUROBORRELIOSIS AND A CERVICAL ANTERIOR HORN LESION

A variety of neurological syndromes has been described in neuroborreliosis: cranial nerve palsies, radiculopathy, axonal neuropathy, stroke, parkinsonism, transverse myelitis, supranuclear palsy, Guillain- Barré syndrome, … We report a case of neuroborreliosis with cervical myelitis presenting clinically as a lower motor neuron syndrome of the upper and lower limbs with proximal and distal pareses and atrophies as well as bulbar dysarthria and dysphagia. During the course of the disease the patient developed the clinical picture of a meningoencephalitis. After initiating ceftriaxone treatment the patient showed a complete recovery.In endemic regions for Lyme disease, in all neurological syndromes neuroborreliosis has to be excluded.

Oculocerebrorenal syndrome of Lowe: magnetic resonance imaging findings in the first six years of life

Oculocerebrorenal syndrome of Lowe: magnetic resonance imaging findings in the first six years of life

Pigmentary Mosaicism, Subcortical Band Heterotopia, and Brain Cystic Lesions

A 10-year-old boy presented with a severe and diffuse mosaic skin hypopigmentation running (in narrow bands) along the lines of Blaschko associated with mosaic areas of alopecia, facial dysmorphism with midface hypoplasia, bilateral punctate cataract, microretrognathia, short neck, pectus excavatum, joint hypermobility, mild muscular hypotonia, generalized seizures, and mild mental retardation. Cranial magnetic resonance imaging revealed hypoplastic corpus callosum (primarily posterior), subcortical band heterotopia, and diffuse subcortical, periventricular cystic-like lesions. Similar dysmorphic features were observed in the child's mother, but with no imaging abnormalities. The facial phenotype coupled with the cysts in the brain was strongly reminiscent of the oculocerebrorenal Lowe syndrome. Full chromosome studies in the parents and the proband and mutation analysis on peripheral blood lymphocytes (and on skin cultured fibroblasts from affected and unaffected skin areas in the child) in the genes for subcortical band heterotopia (DCX (Xq22.3-q23)], lissencephaly (PAFAH1B1, alias LIS1, at 17p13.3), and oculocerebrorenal syndrome of Lowe (OCRL at Xq23-q24)] were unrevealing. This constellation of multiple congenital anomalies including skin hypopigmentation and eye, musculoskeletal, and nervous system abnormalities was sufficiently characterized to be regarded as a novel example of pigmentary mosaicism of the Ito type (i.e., hypomelanosis of Ito).

OCRL1 Mutations in Dent 2 Patients Suggest a Mechanism for Phenotypic Variability

Background/Aims: Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1) or OCRL1 (Dent 2). OCRL1 mutations also cause the oculocerebrorenal syndrome of Lowe. Methods: Dent patients with normal sequence for CLCN5 were sequenced for mutations in OCRL1. By analyzing these and all other OCRL1 mutations reported, a model relating OCRL1 mutations to the resulting disease (Dent 2 or Lowe’s) was developed. Results: Six boys with Dent disease had novel OCRL1 mutations: two missense (R301H, G304E) and four mutations predicted to produce premature termination codons (L56DfsX1, S149X, P161PfsX3, and M170IfsX1). These include one of the original patients reported by Dent and Friedman. Slit lamp examinations revealed early cataracts in only one boy with normal vision. None of these Dent 2 patients had metabolic acidosis; 3 had mild mental retardation. Analysis of all known OCRL1 mutations show that Dent 2 mutations fall into two classes that do not overlap with Lowe mutations. Bioinformatics analyses identified expressed OCRL1 splice variants that help explain the variability of those clinical features that distinguish Dent disease from Lowe syndrome. Conclusions:OCRL1 mutations can cause the renal phenotype of Dent disease, without acidosis or the dramatic eye abnormalities typical of Lowe syndrome. We propose a model to explain the phenotypic variability between Dent 2 and Lowe’s based on distinctly different classes of mutations in OCRL1 producing splice variants.

A case of Lowe syndrome (oculocerebrorenal syndrome): Clinical implications and anaesthetic management

Cataract surgery in neonates and infants can be quite challenging, as many of these children may be having congenital anomalies like Downs, infections like rubella etc. LOWE syndrome is one of the few conditions where the child is born with cataract. LOWE syndrome is a rare X- linked disorder characterised by congenital cataract, mental retardation and Fanconies syndrome. The disease is caused by the mutations of OCRL gene which encodes phospatydyl inositol (4, 5) biphosphatase (Ptdlns (4, 5) P2 phosphatase), protein. We report here the perioperative management of a child with LOWE syndrome who was operated for congenital cataract.

Phosphoinositide phosphatases and disease

The field of inositol signaling has expanded greatly in recent years. Given the many reviews on phosphoinositide kinases, we have chosen to restrict our discussion to inositol lipid hydrolysis focused on the phosphatases and a brief mention of the lipase isoforms. We also discuss recent discoveries that link mutations in phosphoinositide phosphatases to disease.

Differential Clathrin Binding and Subcellular Localization of OCRL1 Splice Isoforms

Mutation of the inositol polyphosphate 5-phosphatase OCRL1 causes the X-linked disorder oculocerebrorenal syndrome of Lowe, characterized by defects in the brain, kidneys, and eyes. OCRL1 exists as two splice isoforms that differ by a single exon encoding 8 amino acids. The longer protein, termed isoform a, is the only form in brain, whereas both isoforms are present in all other tissues. The significance of OCRL1 splicing is currently unclear. Given its proximity to a clathrin-binding site, we hypothesized that splicing may alter the clathrin binding properties of OCRL1. Here we show that this is indeed the case. OCRL1 isoform a binds clathrin with higher affinity than isoform b and is significantly more enriched in clathrin-coated trafficking intermediates. We also identify a second clathrin-binding site in OCRL1 that contributes to clathrin binding of both isoforms. Association of OCRL1 with clathrin-coated intermediates requires membrane association through interaction with Rab GTPases but not binding to the clathrin adaptor AP2. Expression of OCRL1 isoform a lacking the 5-phosphatase domain impairs transferrin endocytosis, whereas an equivalent version of isoform b does not. Our results suggest that OCRL1 exists as two functional pools, one participating in clathrin-mediated trafficking events such as endocytosis and another that is much less or not involved in this process.

The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease

Phosphoinositides are membrane-bound signalling molecules that regulate cell proliferation and survival, cytoskeletal reorganization and vesicular trafficking by recruiting effector proteins to cellular membranes. Growth factor or insulin stimulation induces a canonical cascade resulting in the transient phosphorylation of PtdIns(4,5)P(2) by PI3K (phosphoinositide 3-kinase) to form PtdIns(3,4,5)P(3), which is rapidly dephosphorylated either by PTEN (phosphatase and tensin homologue deleted on chromosome 10) back to PtdIns(4,5)P(2), or by the 5-ptases (inositol polyphosphate 5-phosphatases), generating PtdIns(3,4)P(2). The 5-ptases also hydrolyse PtdIns(4,5)P(2), forming PtdIns4P. Ten mammalian 5-ptases have been identified, which share a catalytic mechanism similar to that of the apurinic/apyrimidinic endonucleases. Gene-targeted deletion of 5-ptases in mice has revealed that these enzymes regulate haemopoietic cell proliferation, synaptic vesicle recycling, insulin signalling, endocytosis, vesicular trafficking and actin polymerization. Several studies have revealed that the molecular basis of Lowe's syndrome is due to mutations in the 5-ptase OCRL (oculocerebrorenal syndrome of Lowe). Futhermore, the 5-ptases SHIP [SH2 (Src homology 2)-domain-containing inositol phosphatase] 2, SKIP (skeletal muscle- and kidney-enriched inositol phosphatase) and 72-5ptase (72 kDa 5-ptase)/Type IV/Inpp5e (inositol polyphosphate 5-phosphatase E) are implicated in negatively regulating insulin signalling and glucose homoeostasis in specific tissues. SHIP2 polymorphisms are associated with a predisposition to insulin resistance. Gene profiling studies have identified changes in the expression of various 5-ptases in specific cancers. In addition, 5-ptases such as SHIP1, SHIP2 and 72-5ptase/Type IV/Inpp5e regulate macrophage phagocytosis, and SHIP1 also controls haemopoietic cell proliferation. Therefore the 5-ptases are a significant family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Emerging studies have implicated their loss or gain of function in human disease.

Oral anomalies associated with the oculocerebrorenal syndrome of Lowe: Case report with multiple unerupted teeth and pericoronal radiolucencies

The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked recessive disorder, chiefly characterized by ocular involvement, mental retardation, and kidney disease. A literature review is provided, detailing the diversity of oral anomalies associated with the OCRL syndrome. Reported abnormalities include delayed tooth eruption, odontogenic cyst formation, and constricted dental arches. In addition, we present an unusual case of an 18-year-old male affected with the OCRL syndrome and fetal alcohol syndrome. The oral radiographic examination was significant for multiple impacted permanent teeth, many with pericoronal radiolucencies, and an underdeveloped mandible.

Abnormal bradykinin signalling in fibroblasts deficient in the PIP2 5‐phosphatase, ocrl1

The oculocerebrorenal syndrome of Lowe (Lowe syndrome) is an X-linked disorder of phosphatidylinositol metabolism characterized by congenital cataracts, renal proximal tubulopathy and neurological deficits. The disorder is due to the deficiency of the phosphatidylinositol 4,5-bisphosphate (PIP(2)) 5-phosphatase, ocrl1. PIP(2) is critical for numerous cellular processes, including cell signalling, actin reorganization and protein trafficking, and is chronically elevated in patients with Lowe syndrome. The elevation of PIP(2) cells of patients with Lowe syndrome provides the unique opportunity to investigate the roles of this phospholipid in fundamental cellular processes. We previously demonstrated that ocrl1 deficiency causes alterations in the actin cytoskeleton. Since actin remodelling is strongly activated by [Ca(+2)], which increases in response to IP(3) production, we hypothesized that altered calcium signalling might contribute to the observed abnormalities in actin organization. Here we report a specific increase in bradykinin-induced Ca(+2) mobilization in Lowe fibroblasts. We show that the abnormal bradykinin signalling occurs in spite of normal total cellular receptor content. These data point to a novel role for ocrl1 in agonist-induced calcium release.

Clinical Features and Surgical Outcomes of Congenital Cataracts in Patients With Oculocerebrorenal Syndrome

Purpose: To describe the clinical features and surgical outcomes of congenital cataracts in patients with oculocerebrorenal syndrome. Methods: We retrospectively analyzed the age, sex, types of cataracts, operation method and time, perioperative visual acuity, postoperative intraocular pressure, and associated ocular disease in 10 patients (20 eyes) that had been diagnosed with congenital cataracts associated with oculocerebrorenal syndrome and undergone cataract surgery with a minimum follow-up period of 1 year. Results: All 10 patients were male and had bilateral cataracts detected on their first full ophthalmic examination. The mean age at diagnosis was 2.5 (2.51.4) months, and the mean duration of the follow-up period was 4.9 (4.94.2) years. The types of cataracts were nuclear sclerosis in 18 eyes of nine patients and cortical opacity in two eyes of one patient. All patients underwent irrigation and aspiration of the lenses, posterior capsulectomy and anterior vitrectomy in both eyes before the age of 1 year. Nine patients (18 eyes) underwent cataract extraction before the age of 6 months, and three patients (6 eyes) underwent the surgery before the age of 2 months. Secondary intraocular lens implantation was done in six eyes of three patients at the age of 34 (3413.2) months. Postoperative best corrected visual acuity ranged from light perception to 0.15. Out of the nine patients who underwent cataract extraction before the age of 6 months, seven patients could fix and follow objects moderately. The visual acuity of patient who underwent cataract extraction of each eye at the age of 9 months and 12 months was hand motion. In addition to cataracts, glaucoma occurred in three eyes of two patients, corneal opacity in two eyes of one patient and strabismus in three patients. Conclusions: Visual acuity after cataract surgery was poor in patients with oculocerebrorenal syndrome, especially when the diagnosis and surgery was delayed. Earlier identification and surgical removal of cataracts is recommended. Patients should be monitored regularly for other ocular diseases such as glaucoma, corneal opacity and strabismus.

Association between severity of lower urinary tract symptoms, erectile dysfunction and metabolic syndrome

Introduction. The purpose of this study was to investigate the association between severity of lower urinary tract symptoms (LUTS), erectile dysfunction (ED) and metabolic syndrome.Methods. Our study population included a consecutive series of 190 patients with LUTS (International Prostate Symptom Score-IPSS >7) with or without manifestations of the metabolic syndrome. The diagnoses of diabetes mellitus and hypertension were obtained from the patient's medical history. Data on blood pressure, waist measure, body height and weight were collected and body mass index were calculated. Patients were assessed based on the International Index of Erectile Function (IIEF) for ED and IPSS and IPSS-Quality of Life for LUTS. Blood samples were drawn from fasting patients to determine, fasting blood glucose (FBG), triglycerides, HDL-cholesterol and serum total testosterone levels.Results. In severe LUTS patient group, IIEF erectile function domain scores were significantly lower than moderate LUTS patient group (p < 0.05). Multiple logistic regression analysis confirmed that presence of ED was the most predictor of severe LUTS. The prevalence of metabolic syndrome was higher in patients with severe LUTS (26%vs. 46%, p = 0.009). The severe form of the LUTS was significantly correlated with waist circumference >102 cm (p < 0.05), blood pressure ≥130/85 mmHg (p < 0.05) and FBG >110 mg/dl (p < 0.01).Conclusion. Obesity, high plasma level of FBG and hypertension constitute risk factors for the development of severe LUTS. Metabolic syndrome may play a key role in the pathogenesis in both ED and LUTS. Presence of ED is the most predictor of severe LUTS.

The perioperative management of a patient with lowe syndrome for general anesthesia: A case report.

Lowe syndrome (the oculo-cerebro-renal syndrome of Lowe, OCRL) is a multi-system disorder that affects the eyes, nervous system, and kidney. OCRL is a rare X-linked recessive disease with a prevalence of approximately 1 : 500,000. The clinical features of OCRL include congenital cataracts, growth and mental retardation, areflexia, hypotonia, and renal tubular dysfunction (Fanconi-type). Chronic metabolic acidosis and hypotonia may be the most important component affecting management of the peri-anesthetic period during general anesthesia. However, problems such as electrolyte imbalance, seizure, fragility of the bone structures, and increased intraocular pressure should also be considered during the perioperative period. We report here the perioperative management of a patient with Lowe syndrome during the removal of multiple scalp cysts under general anesthesia.