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Robert L Nussbaum - One of the best experts on this subject based on the ideXlab platform.
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kidney tubular ablation of ocrl inpp5b phenocopies lowe Syndrome tubulopathy
Journal of The American Society of Nephrology, 2017Co-Authors: Kazunori Inoue, Robert L Nussbaum, Daniel M Balkin, Lijuan Liu, Ramiro Nandez, Xuefei Tian, Tong WangAbstract: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.
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mouse model for lowe Syndrome dent disease 2 renal tubulopathy
Journal of The American Society of Nephrology, 2011Co-Authors: Susan P Bothwell, Emily Chan, William A. Gahl, Isa Bernardini, Robert L NussbaumAbstract:The Lowe Oculocerebrorenal Syndrome is an X-linked disorder characterized by congenital cataracts, cognitive disability, and proximal tubular dysfunction. Both this Syndrome and Dent Disease 2 result from loss-of-function mutations in the OCRL gene, which encodes a type II phosphatidylinositol bisphosphate 5-phosphatase. Ocrl-deficient mice are unaffected, however, which we believe reflects a difference in how humans and mice cope with the enzyme deficiency. Inpp5b and INPP5B, paralogous autosomal genes that encode another type II phosphoinositide 5-phosphatase in mice and humans, respectively, might explain the distinct phenotype in the two species because they are the closest paralogs to Ocrl and OCRL in their respective genomes yet differ between the two species with regard to expression and splicing. Here, we generated Ocrl(-/-) mice that express INPP5B but not Inpp5b. Similar to the human Syndromes, all showed reduced postnatal growth, low molecular weight proteinuria, and aminoaciduria. Thus, we created an animal model for OCRL and Dent Disease 2 tubulopathy by humanizing a modifier paralog in mice already carrying the mutant disease gene.
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functional overlap between murine inpp5b and ocrl1 may explain why deficiency of the murine ortholog for ocrl1 does not cause lowe Syndrome in mice
Journal of Clinical Investigation, 1998Co-Authors: Pasi A Janne, Sharon F Suchy, David J Bernard, Michael Macdonald, Jacqueline N Crawley, Alexander Grinberg, Anthony Wynshawboris, Heiner Westphal, Robert L NussbaumAbstract:The Oculocerebrorenal Syndrome of Lowe (OCRL) is an X-linked human genetic disorder characterized by mental retardation, congenital cataracts, and renal tubular dysfunction. The Lowe Syndrome gene, OCRL1, encodes a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex. The pathogenesis of Lowe Syndrome due to deficiency of a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex is unknown. We have used targeted disruption in embryonic stem cells to make mice deficient in Ocrl1, the mouse homologue for OCRL1, as an animal model for the disease. Surprisingly, mice deficient in Ocrl1 do not develop the congenital cataracts, renal Fanconi Syndrome, or neurological abnormalities seen in the human disorder. We hypothesized that Ocrl1 deficiency is complemented in mice by inositol polyphosphate 5-phosphatase (Inpp5b), an autosomal gene that encodes a phosphatidylinositol bisphosphate 5-phosphatase highly homologous to Ocrl1. We created mice deficient in Inpp5b; the mice were viable and fertile without phenotype except for testicular degeneration in males beginning after sexual maturation. We crossed mice deficient in Ocrl1 to mice deficient in Inpp5b. No liveborn mice or embryos lacking both enzymes were found, demonstrating that Ocrl1 and Inpp5b have overlapping functions in mice and suggesting that the lack of phenotype in Ocrl1-deficient mice may be due to compensating Inpp5b function.
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spectrum of mutations in the ocrl1 gene in the lowe Oculocerebrorenal Syndrome
American Journal of Human Genetics, 1997Co-Authors: Ti Lin, Richard A. Lewis, Annmarie Leahey, Bonnie M Orrison, Sharon F Suchy, David J Bernard, Robert L NussbaumAbstract:The Oculocerebrorenal Syndrome of Lowe (OCRL) is a multisystem disorder characterized by congenital cataracts, mental retardation, and renal Fanconi Syndrome. The OCRL1 gene, which, when mutated, is responsible for OCRL, encodes a 105-kD Golgi protein with phosphatidylinositol (4,5)bisphosphate (PtdIn[4,5]P2) 5-phosphatase activity. We have examined the OCRL1 gene in 12 independent patients with OCRL and have found 11 different mutations. Six were nonsense mutations, and one a deletion of one or two nucleotides that leads to frameshift and premature termination. In one, a 1.2-kb genomic deletion of exon 14 was identified. In four others, missense mutations or the deletion of a single codon were found to involve amino acid residues known to be highly conserved among proteins with PtdIns(4,5)P2 5-phosphatase activity. All patients had markedly reduced PtdIns(4,5)P2 5-phosphatase activity in their fibroblasts, whereas the ocrl1 protein was detectable by immunoblotting in some patients with either missense mutations or a codon deletion but was not detectable in those with premature termination mutations. These results confirm and extend our previous observation that the OCRL phenotype results from loss of function of the ocrl1 protein and that mutations are generally heterogeneous. Missense mutations that abolish enzyme activity but not expression of the protein will be useful for studying structure-function relationships in PtdIns(4,5)P2 5-phosphatases.
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the Oculocerebrorenal Syndrome gene product is a 105 kd protein localized to the golgi complex
American Journal of Human Genetics, 1995Co-Authors: I M Olivosglander, Pasi A Janne, Robert L NussbaumAbstract:The Oculocerebrorenal Syndrome of Lowe (OCRL) is a multisystem disorder affecting the lens, kidney, and CNS. The predicted amino acid sequence of the OCRL gene, OCRL-1, was used to develop antibodies against the OCRL-1 protein. Western blot analysis using affinity-purified serum against the amino terminus of the OCRL-1 gene product (ocrl-1) demonstrates a single protein of 105 kD in fibroblasts of a normal individual that is absent in fibroblasts of an OCRL patient who lacks OCRL-1 transcript. A single protein with the same electrophoretic mobility is found by western analysis in various human cultured cell lines, and approximately the same size protein is also found in all mouse tissues tested. Northern analysis of various human and mouse tissues demonstrate that OCRL-1 transcript is expressed in nearly all tissues examined. By immunofluorescence, the ocrl-1 antibody stains a juxtanuclear region in normal fibroblast cells, while no specific staining is evident in the OCRL patient who produces no transcript. Colocalization of the ocrl-1 protein to the Golgi complex was demonstrated using a known monoclonal antibody against a Golgi-specific coat protein, beta-COP (beta coatomer protein).
Yang Sun - One of the best experts on this subject based on the ideXlab platform.
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Oculocerebrorenal Syndrome of lowe survey of ophthalmic presentations and management
European Journal of Ophthalmology, 2020Co-Authors: Ke Ning, Yang Sun, Sayena Jabbehdari, Philipp P Prosseda, Ann Shue, Scott R LambertAbstract:BackgroundLowe Syndrome is a rare X-linked disease that is characterized by renal dysfunction, developmental delays, congenital cataracts and glaucoma. Mutations in the oculocerebral renal Syndrome...
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loss of ocrl increases ciliary pi 4 5 p2 in lowe Oculocerebrorenal Syndrome
PMC, 2017Co-Authors: Philipp P Prosseda, Na Luo, Jorge A Alvarado, Yang Sun, Biao WangAbstract:ABSTRACT 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)P 2 , 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)P 2 and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P 2 build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P 2 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)P 2 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.
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ocular pathology of Oculocerebrorenal Syndrome of lowe novel mutations and genotype phenotype analysis
Scientific Reports, 2017Co-Authors: Emilie Song, Na Luo, Jorge A Alvarado, Maria Lim, Cathleen Walnuss, Daniel Neely, Dan Spandau, Alireza Ghaffarieh, Yang SunAbstract: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.
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compensatory role of inositol 5 phosphatase inpp5b to ocrl in primary cilia formation in Oculocerebrorenal Syndrome of lowe
PLOS ONE, 2013Co-Authors: Na Luo, Akhilesh Kumar, Michael Conwell, Robert N Weinreb, Ryan Anderson, Yang SunAbstract:Inositol phosphatases are important regulators of cell signaling, polarity, and vesicular trafficking. Mutations in OCRL, an inositol polyphosphate 5-phosphatase, result in Oculocerebrorenal Syndrome of Lowe, an X-linked recessive disorder that presents with congenital cataracts, glaucoma, renal dysfunction and mental retardation. INPP5B is a paralog of OCRL and shares similar structural domains. The roles of OCRL and INPP5B in the development of cataracts and glaucoma are not understood. Using ocular tissues, this study finds low levels of INPP5B present in human trabecular meshwork but high levels in murine trabecular meshwork. In contrast, OCRL is localized in the trabecular meshwork and Schlemm’s canal endothelial cells in both human and murine eyes. In cultured human retinal pigmented epithelial cells, INPP5B was observed in the primary cilia. A functional role for INPP5B is revealed by defects in cilia formation in cells with silenced expression of INPP5B. This is further supported by the defective cilia formation in zebrafish Kupffer’s vesicles and in cilia-dependent melanosome transport assays in inpp5b morphants. Taken together, this study indicates that OCRL and INPP5B are differentially expressed in the human and murine eyes, and play compensatory roles in cilia development.
William A. Gahl - One of the best experts on this subject based on the ideXlab platform.
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mouse model for lowe Syndrome dent disease 2 renal tubulopathy
Journal of The American Society of Nephrology, 2011Co-Authors: Susan P Bothwell, Emily Chan, William A. Gahl, Isa Bernardini, Robert L NussbaumAbstract:The Lowe Oculocerebrorenal Syndrome is an X-linked disorder characterized by congenital cataracts, cognitive disability, and proximal tubular dysfunction. Both this Syndrome and Dent Disease 2 result from loss-of-function mutations in the OCRL gene, which encodes a type II phosphatidylinositol bisphosphate 5-phosphatase. Ocrl-deficient mice are unaffected, however, which we believe reflects a difference in how humans and mice cope with the enzyme deficiency. Inpp5b and INPP5B, paralogous autosomal genes that encode another type II phosphoinositide 5-phosphatase in mice and humans, respectively, might explain the distinct phenotype in the two species because they are the closest paralogs to Ocrl and OCRL in their respective genomes yet differ between the two species with regard to expression and splicing. Here, we generated Ocrl(-/-) mice that express INPP5B but not Inpp5b. Similar to the human Syndromes, all showed reduced postnatal growth, low molecular weight proteinuria, and aminoaciduria. Thus, we created an animal model for OCRL and Dent Disease 2 tubulopathy by humanizing a modifier paralog in mice already carrying the mutant disease gene.
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clinical and laboratory findings in the Oculocerebrorenal Syndrome of lowe with special reference to growth and renal function
The New England Journal of Medicine, 1991Co-Authors: Lawrence R Charnas, Isa Bernardini, Daniel J Rader, Jeffrey M Hoeg, William A. GahlAbstract:Abstract Background. The Oculocerebrorenal Syndrome of Lowe is an X-linked disorder whose clinical manifestations include congenital cataracts, mental retardation, and renal tubular dysfunction. We investigated growth, renal function, and serum chemistry values in patients with the Oculocerebrorenal Syndrome to determine the natural history of the disorder and its heterogeneity with respect to these characteristics. Methods. Twenty-three patients with the Oculocerebrorenal Syndrome, ranging in age from 4 months to 31 years, were examined. Height was compared with bone age. Renal function was assessed by measurements of proteinuria, urinary volume, and fractional excretions of potassium, phosphate, carnitine, and amino acids. Creatinine clearance was determined as a measure of glomerular function. Results. In the Oculocerebrorenal Syndrome, linear growth decreases after one year of age; bone age lies between chronologic age and height age. Renal dysfunction occurs in the first year of life, characterized b...
Michael Ludwig - One of the best experts on this subject based on the ideXlab platform.
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The Oculocerebrorenal Syndrome of Lowe: an update
Pediatric Nephrology, 2016Co-Authors: Arend Bökenkamp, Michael LudwigAbstract:The Oculocerebrorenal Syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and proximal renal tubular dysfunction. Whereas the ocular manifestations and severe muscular hypotonia are the typical first diagnostic clues apparent at birth, the manifestations of incomplete renal Fanconi Syndrome are often recognized only later in life. Other characteristic features are progressive severe growth retardation and behavioral problems, with tantrums. Many patients develop a debilitating arthropathy. Treatment is symptomatic, and the life span rarely exceeds 40 years. The causative Oculocerebrorenal Syndrome of Lowe gene ( OCRL ) encodes the inositol polyphosphate 5-phosphatase OCRL-1. OCRL variants have not only been found in classic Lowe Syndrome, but also in patients with a predominantly renal phenotype classified as Dent disease type 2 (Dent-2). Recent data indicate that there is a phenotypic continuum between Dent-2 disease and Lowe Syndrome, suggesting that there are individual differences in the ability to compensate for the loss of enzyme function. Extensive research has demonstrated that OCRL-1 is involved in multiple intracellular processes involving endocytic trafficking and actin skeleton dynamics. This explains the multi-organ manifestations of the disease. Still, the mechanisms underlying the wide phenotypic spectrum are poorly understood, and we are far from a causative therapy. In this review, we provide an update on clinical and molecular genetic findings in Lowe Syndrome and the cellular and physiological functions of OCRL-1.
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novel ocrl mutations in patients with dent 2 disease
Journal of pediatric genetics, 2015Co-Authors: Detlef Böckenhauer, Kristina Vrljicak, Tony Sirimanna, Robert J Unwin, William Vant Hoff, Matti Nuutinen, Arend Bökenkamp, Michael LudwigAbstract:Dent disease is an X-linked tubulopathy frequently caused by mutations in the CLCN5 gene encoding the voltage-gated chloride channel and chloride/proton antiporter, ClC-5. About 15% of patients with a Dent' phenotype have mutations in the OCRL gene, which also causes Lowe Oculocerebrorenal Syndrome. To distinguish these patients from the more severe Lowe phenotype, they are diagnosed as having Dent-2 disease. We studied 14 CLCN5-negative patients from 12 families with a phenotype resembling Dent disease for defects in OCRL. In six of these kindreds three novel (c.149+1G>A, c.1126A>T, c.1547T>C) and three repeatedly observed mutations (c.166_167delTT, c.901C>T, c.1426C>T) were discovered. With the exception of a lower prevalence of nephrocalcinosis, the renal phenotype is identical with patients harboring a CLCN5 mutation. Affected children may have some of the extra-renal symptoms of Lowe Syndrome, such as peripheral cataracts, mental impairment, stunted growth or elevation of creatine kinase/lactate dehydrogenase, blurring the distinction between those two clinical entities.
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lowe Syndrome dent 2 disease a comprehensive review of known and novel aspects
Journal of pediatric genetics, 2015Co-Authors: Florian Recker, Michael Ludwig, Heiko ReutterAbstract:The Oculocerebrorenal Syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, cognitive and behavioral impairment and a renal proximal tubulopathy in almost all of the patients. Whereas the ocular manifestations and severe hypotonia are present at birth, the renal involvement appears within the first months of life. Patients show progressive growth retardation and may develop a debilitating arthropathy. Treatment is symptomatic and life span rarely exceeds 40 yr. The causative OCRL gene, encodes an inositol polyphosphate 5-phosphatase. OCRL mutations were not only found in classic Lowe Syndrome, but also in milder affected patients, classified as having Dent-2 disease. There is a phenotypic continuum within patients with Dent-2 disease and Lowe Syndrome, suggesting that there are individual differences in the ability to compensate for loss of enzyme function. Researchers have conducted a large amount of work to understand the etiology responsible for the disease. However, the mechanisms leading to the clinical manifestations are still poorly understood and we are far from an effective therapy. In this review, we have included well-established findings and the most recent progress in understanding Lowe Syndrome and Dent-2 disease.
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selective proximal renal tubular involvement and dyslipidemia in two cousins with Oculocerebrorenal Syndrome of lowe
Turkish Journal of Pediatrics, 2013Co-Authors: R Topaloglu, Michael Ludwig, Celebi Tayfur AAbstract:Oculocerebrorenal Syndrome of Lowe (OCRL) is a rare, X-linked disorder characterized by congenital cataracts, neonatal or infantile hypotonia, seizures, cognitive impairment, and renal tubular dysfunction. In this article, we report two maternal cousins with OCRL with a hemizygous p.Ala788Asp mutation in exon 22 of the OCRL gene. They presented with diverse features of selective proximal renal tubular defect and high serum levels of total cholesterol, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C).
Lawrence R Charnas - One of the best experts on this subject based on the ideXlab platform.
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Evidence for a discrete behavioral phenotype in the Oculocerebrorenal Syndrome of lowe
American journal of medical genetics, 1995Co-Authors: Lauren Kenworthy, Lawrence R CharnasAbstract:The Oculocerebrorenal Syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, cognitive impairment, and renal tubular dysfunction. Although there is a wide range of intellectual function in affected individuals, it is often compromised by a high prevalence of maladaptive behaviors, including tantrums, stubbornness, and stereotypy. Whether these behaviors simply reflect the multiple disabilities found in some developmentally impaired individuals with or without OCRL, or a specific genetically-determined behavioral phenotype of OCRL, is unknown. Controls were matched for sex, age, visual impairment, and adaptive functioning and compared with OCRL patients on three standardized measures of adaptive/maladaptive behaviors. Forty-three matched pairs of OCRL and control subjects were identified. Both groups were similar in communication, daily living, socialization, and motor skills, in socioeconomic status, and in measures of parental stress. Individuals with OCRL displayed significantly more severe maladaptive behaviors than control boys, as measured by the Vineland Adaptive Behavior Scales (VABS), with 41% of the difference between the two groups attributable to the diagnosis of OCRL. Twelve maladaptive behaviors measured on the VABS appeared more frequently in OCRL than in controls. Five of these 12 behaviors, i.e., temper tantrums, irritability, complex repetitive behaviors (stereotypy)/mannerisms, obsessions/unusual preoccupations, and negativism, were identifiedmore » by discriminant function analysis to significantly distinguish between controls and OCRL individuals. The diagnosis of OCRL is associated with a behavioral phenotype consisting of temper tantrums, stereotypy, stubbornness, and obsessions/unusual preoccupations. This phenotype cannot be attributed solely to the visual, motor, and intellectual disabilities characteristic of OCRL, and may represent a specific effect of the OCRL gene on the central nervous system. 57 refs., 5 tabs.« less
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fetal Oculocerebrorenal Syndrome of lowe associated with elevated maternal serum and amniotic fluid alpha fetoprotein levels
Obstetrics & Gynecology, 1994Co-Authors: Richard C Miller, Edward J Wolf, Margot Gould, Charles J Macri, Lawrence R CharnasAbstract:OBJECTIVE To report an association between fetal Oculocerebrorenal Syndrome of Lowe and elevations in maternal serum alpha-fetoprotein (MSAFP) and amniotic fluid alpha-fetoprotein (AFAFP). METHODS Case 1 was identified during routine MSAFP screening. Cases 2-5 were identified through review of a data base of individuals with Oculocerebrorenal Syndrome enrolled at the National Institutes of Health. To estimate the frequency of this association, only those whose mothers would have been in the early second trimester from February 1987 to August 1993 were enumerated. The MSAFP was assumed to be normal unless explicitly reported or unless information outside the data base confirmed that MSAFP was not determined. RESULTS An elevated MSAFP (2.5 multiples of the median [MoM] or greater) was detected in five of 20 pregnancies with a fetus affected by Oculocerebrorenal Syndrome. Maternal serum alpha-fetoprotein was greater than 5.0 MoM in three pregnancies undergoing amniocentesis, and all had an elevated AFAFP without significant acetylcholinesterase activity. No abnormalities were found by ultrasound, and there was no other cause of elevated AFP identified postnatally. Family history was positive in three of the five cases. The mothers were carriers in four of the five cases, whereas the fifth case appeared to be a spontaneous mutation. CONCLUSIONS Elevated MSAFP and AFAFP appear to occur at a higher than expected frequency in pregnancies carrying an Oculocerebrorenal Syndrome fetus. The mechanism of elevation of AFP may be related to fetal renal tubular dysfunction. A directed interview, focusing on a maternal family history of male relatives with unexplained mental retardation, early institutionalization, or congenital rubella, is appropriate with unexplained MSAFP elevations and, particularly, with unexplained AFAFP elevations without acetylcholinesterase activity.
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cognitive and behavioral profile of the Oculocerebrorenal Syndrome of lowe
American Journal of Medical Genetics, 1993Co-Authors: Lauren Kenworthy, Taesung Park, Lawrence R CharnasAbstract:Background: The Oculocerebrorenal Syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, cognitive impairment, and renal tubular dysfunction. Significant behavioral difficulties have been reported, but no formal study of intelligence or behavior has been described. Methods: We surveyed IQ and behavior using archival data and standardized instruments in 47 affected males. Results: Mean IQ was in the moderate mental retardation range (40 ≤ IQ ≤ 54), with 25% of tested individuals in normal range (IQ ≥ 70). The OCRL population was comparable to a normative population with mental retardation in language, communication, and socialization skills, but lower in independent living skills than means of either populations of individuals with mental retardation or visual impairment. Maladaptive behaviors, particularly stubbornness, temper tantrums, and stereotypic behaviors, were very frequent (>80%). Conclusions: The diagnosis of OCRL is compatible with normal intelligence. Maladaptive behaviors significantly interfere with adaptive functions. These behaviors appear to define a characteristic behavioral phenotype in OCRL. © 1993 Wiley-Liss, Inc.
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nonsense mutations in the ocrl 1 gene in patients with the Oculocerebrorenal Syndrome of lowe
Human Molecular Genetics, 1993Co-Authors: Annmarie Leahey, Lawrence R Charnas, Robert L NussbaumAbstract:A candidate gene, OCRL-1, for the Oculocerebrorenal Syndrome of Lowe (OCRL) has been identified via positional cloning strategies. We have now developed RT-PCR techniques which allow amplification of nearly all of the open reading frame from total RNA and have used the PCR products for mutational analysis. Single strand conformational polymorphism analysis detected aberrant migration in two unrelated patients, both of whom were shown to have the same nonsense mutation at base 2746 on direct sequencing. An additional patient was found to be missing a segment from his RNA that corresponds to an entire exon. The identification of mutations in the OCRL-1 gene provides strong genetic evidence for its being the gene involved in Lowe Syndrome.
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clinical and laboratory findings in the Oculocerebrorenal Syndrome of lowe with special reference to growth and renal function
The New England Journal of Medicine, 1991Co-Authors: Lawrence R Charnas, Isa Bernardini, Daniel J Rader, Jeffrey M Hoeg, William A. GahlAbstract:Abstract Background. The Oculocerebrorenal Syndrome of Lowe is an X-linked disorder whose clinical manifestations include congenital cataracts, mental retardation, and renal tubular dysfunction. We investigated growth, renal function, and serum chemistry values in patients with the Oculocerebrorenal Syndrome to determine the natural history of the disorder and its heterogeneity with respect to these characteristics. Methods. Twenty-three patients with the Oculocerebrorenal Syndrome, ranging in age from 4 months to 31 years, were examined. Height was compared with bone age. Renal function was assessed by measurements of proteinuria, urinary volume, and fractional excretions of potassium, phosphate, carnitine, and amino acids. Creatinine clearance was determined as a measure of glomerular function. Results. In the Oculocerebrorenal Syndrome, linear growth decreases after one year of age; bone age lies between chronologic age and height age. Renal dysfunction occurs in the first year of life, characterized b...
