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European Journal of Ophthalmology Sep 2020Lowe syndrome is a rare X-linked disease that is characterized by renal dysfunction, developmental delays, congenital cataracts and glaucoma. Mutations in the...
BACKGROUND
Lowe 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 of Lowe () gene are found in Lowe syndrome patients. Although loss of vision is a major concern for families and physicians who take care of Lowe syndrome children, definitive cause of visual loss is still unclear. Children usually present with bilateral dense cataracts at birth and glaucoma, which occurs in more than half of cases, either concurrently or following cataract surgery.
MATERIALS AND METHODS
A retrospective review was conducted on the prevalence and characteristics of ocular findings among families of patients with Lowe syndrome with 137 uniquely affected individuals.
RESULTS
Of 137 patients, all had bilateral congenital cataracts. Nystagmus was reported in 69.3% of cases, glaucoma in 54.7%, strabismus in 35.0%, and corneal scar in 18.2% of patients. Glaucoma was reported as the most common cause of blindness (46%) followed by corneal scars (41%). Glaucoma occurred in 54.7% of patients and affected both eyes in the majority of cases. Of these patients, 55% underwent surgery for glaucoma, while the remaining patients used medications to control their eye pressure. Timolol and latanoprost were the most commonly used medications. Although trabeculectomy and goniotomy are commonly used for pressure management, aqueous tube shunts had the best outcomes.
CONCLUSION
Ocular manifestations in individuals with Lowe syndrome and carriers with mutation are reported which may help familiarize clinicians with the ocular manifestations and management of a rare and complex syndrome.
Topics: Cataract; Cataract Extraction; Child; Child, Preschool; Corneal Diseases; Eye Diseases; Female; Glaucoma; Humans; Infant; Infant, Newborn; Male; Nystagmus, Pathologic; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases; Prevalence; Retrospective Studies; Strabismus
PubMed: 32340490
DOI: 10.1177/1120672120920544 -
Pediatric Nephrology (Berlin, Germany) Dec 2016The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and... (Review)
Review
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.
Topics: Adolescent; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 11; Humans; Infant; Infant, Newborn; Molecular Biology; Mutation; Oculocerebrorenal Syndrome; WAGR Syndrome
PubMed: 27011217
DOI: 10.1007/s00467-016-3343-3 -
Orphanet Journal of Rare Diseases May 2006Lowe syndrome (the oculocerebrorenal syndrome of Lowe, OCRL) is a multisystem disorder characterised by anomalies affecting the eye, the nervous system and the kidney.... (Review)
Review
Lowe syndrome (the oculocerebrorenal syndrome of Lowe, OCRL) is a multisystem disorder characterised by anomalies affecting the eye, the nervous system and the kidney. It is a uncommon, panethnic, X-linked disease, with estimated prevalence in the general population of approximately 1 in 500,000. Bilateral cataract and severe hypotonia are present at birth. In the subsequent weeks or months, a proximal renal tubulopathy (Fanconi-type) becomes evident and the ocular picture may be complicated by glaucoma and cheloids. Psychomotor retardation is evident in childhood, while behavioural problems prevail and renal complications arise in adolescence. The mutation of the gene OCRL1 localized at Xq26.1, coding for the enzyme phosphatidylinositol (4,5) bisphosphate 5 phosphatase, PtdIns (4,5)P2, in the trans-Golgi network is responsible for the disease. Both enzymatic and molecular testing are available for confirmation of the diagnosis and for prenatal detection of the disease. The treatment includes: cataract extraction, glaucoma control, physical and speech therapy, use of drugs to address behavioural problems, and correction of the tubular acidosis and the bone disease with the use of bicarbonate, phosphate, potassium and water. Life span rarely exceeds 40 years.
Topics: Adolescent; Adult; Central Nervous System Diseases; Child; Child, Preschool; Diagnosis, Differential; Eye Diseases; Female; Genetic Carrier Screening; Humans; Infant; Infant, Newborn; Kidney Diseases; Middle Aged; Oculocerebrorenal Syndrome; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Pregnancy; Prenatal Diagnosis; Prognosis; Quality of Life; Young Adult
PubMed: 16722554
DOI: 10.1186/1750-1172-1-16 -
Scientific Reports May 2017Mutations in the OCRL1 gene result in the oculocerebrorenal syndrome of Lowe, with symptoms including congenital bilateral cataracts, glaucoma, renal failure, and...
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)P). 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.
Topics: Eye; Genotype; Glaucoma; Humans; Keratinocytes; Male; Mutation, Missense; Oculocerebrorenal Syndrome; Pedigree; Phenotype; Phosphoric Monoester Hydrolases; Protein Structure, Tertiary; Sequence Deletion
PubMed: 28473699
DOI: 10.1038/s41598-017-01447-3 -
The Journal of Biological Chemistry Jun 2023T-cell acute lymphoblastic leukemia (T-ALL) is one of the deadliest and most aggressive hematological malignancies, but its pathological mechanism in controlling cell...
T-cell acute lymphoblastic leukemia (T-ALL) is one of the deadliest and most aggressive hematological malignancies, but its pathological mechanism in controlling cell survival is not fully understood. Oculocerebrorenal syndrome of Lowe is a rare X-linked recessive disorder characterized by cataracts, intellectual disability, and proteinuria. This disease has been shown to be caused by mutation of oculocerebrorenal syndrome of Lowe 1 (OCRL1; OCRL), encoding a phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] 5-phosphatase involved in regulating membrane trafficking; however, its function in cancer cells is unclear. Here, we uncovered that OCRL1 is overexpressed in T-ALL cells, and knockdown of OCRL1 results in cell death, indicating the essential role of OCRL in controlling T-ALL cell survival. We show OCRL is primarily localized in the Golgi and can translocate to plasma membrane (PM) upon ligand stimulation. We found OCRL interacts with oxysterol-binding protein-related protein 4L, which facilitates OCRL translocation from the Golgi to the PM upon cluster of differentiation 3 stimulation. Thus, OCRL represses the activity of oxysterol-binding protein-related protein 4L to prevent excessive PI(4,5)P hydrolysis by phosphoinositide phospholipase C β3 and uncontrolled Ca release from the endoplasmic reticulum. We propose OCRL1 deletion leads to accumulation of PI(4,5)P in the PM, disrupting the normal Ca oscillation pattern in the cytosol and leading to mitochondrial Ca overloading, ultimately causing T-ALL cell mitochondrial dysfunction and cell death. These results highlight a critical role for OCRL in maintaining moderate PI(4,5)P availability in T-ALL cells. Our findings also raise the possibility of targeting OCRL1 to treat T-ALL disease.
Topics: Humans; Cell Membrane; Cell Survival; Hydrolysis; Oculocerebrorenal Syndrome; Phosphatidylinositol 4,5-Diphosphate; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Phosphoric Monoester Hydrolases; Golgi Apparatus; Ligands; Protein Transport; Calcium Signaling; Mitochondria; Cytosol
PubMed: 37172724
DOI: 10.1016/j.jbc.2023.104812 -
Ugeskrift For Laeger Feb 2014Although many congenital diseases present disturbances of the central nervous system, eyes and renal function, only few of these have a defined genetic basis. The first... (Review)
Review
Although many congenital diseases present disturbances of the central nervous system, eyes and renal function, only few of these have a defined genetic basis. The first clinical features of cerebro-oculo-renal diseases usually develop in early childhood and deterioration of kidney function and even end-stage kidney disease may occur in a young age. The syndromes should be considered in patients with retarded growth and development, central nervous system abnormalities, impaired vision or blindness and progressive renal failure.
Topics: Abnormalities, Multiple; Bardet-Biedl Syndrome; Cerebellar Diseases; Cerebellum; Child; Cilia; Ciliary Motility Disorders; Ciliopathies; Encephalocele; Eye Abnormalities; Genetic Predisposition to Disease; Humans; Kidney Diseases, Cystic; Leber Congenital Amaurosis; Oculocerebrorenal Syndrome; Optic Atrophies, Hereditary; Polycystic Kidney Diseases; Retina; Retinitis Pigmentosa
PubMed: 25350305
DOI: No ID Found -
BMC Medical Genomics Sep 2021Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by congenital cataracts, mental retardation, and proximal tubulopathy. This condition is...
BACKGROUND
Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by congenital cataracts, mental retardation, and proximal tubulopathy. This condition is caused by a mutation of OCRL gene (located at chromosome Xq26.1), which encodes an inositol polyphosphate 5-phosphatase.
CASE PRESENTATION
We identified two novel OCRL mutations in two unrelated Chinese boys, each with a severe phenotype of Lowe syndrome. A novel de novo deletion (hemizygous c.659_662delAGGG, p.E220Vfs*29) was present in patient 1 and a novel splicing mutation (hemizygous c.2257-2A > T) that was maternally inherited was present in patient 2. A renal biopsy in patient 2 indicated mild mesangial proliferative glomerulonephritis, mild focal mononuclear cells infiltration, and interstitial focal fibrosis. Moreover, renal expression of OCRL-1 protein in patient 2 was significantly reduced compared to a control patient with thin basement membrane disease.
CONCLUSIONS
This study reports two novel OCRL variants associated with severe ocular and neurologic deficiency, despite only mild renal dysfunction. Based on our two patients and a literature review, the genotype-phenotype correlation of OCRL mutations with this severe phenotype of Lowe syndrome suggest a possible clustering of missense, deletion, and nonsense mutations in the 5-phosphatase domain and Rho-GAP domain in the Chinese population.
Topics: Oculocerebrorenal Syndrome
PubMed: 34488756
DOI: 10.1186/s12920-021-01069-9