Overview: a rare multisystemic disorder
The Oculocerebrorenal syndrome of Lowe (OCRL) is a X-linked multisystemic disorder with the hallmark features of congenital cataracts, renal disease and mental retardation. The causative gene, OCRL1, contains 24 exons and encodes the OCRL1 protein, an inositol polyphosphate 5 phosphathase. Lowe syndrome can be also considered closely related to Fanconi syndrome characterized by bicarbonaturia, renal tubular acidosis, aminoaciduria, phosphaturia, tubular proteinuria, and impaired urine-concentrating ability.
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Structure and Function of the Lowe Syndrome Protein OCRL1, 2005
In 1952, the condition became known as "Lowe syndrome" named after Dr. Charles Lowe, the senior member of the group that described it. Dr. Lowe reported the histories of three unrelated male infants (with photographs of two of them) who shared the distinctive characteristics of bilateral dense congenital cataracts, congenital glaucoma and “hydrophthalmos”, developmental retardation, hyporeflexia with motor hyperactivity, flabby musculature but abundant subcutaneous fat, frontal bossing, metabolic acidosis, albuminuria and aminoaciduria without phosphaturia, bone demineralization or osteopenia and rickets, decreased ammonia production, and a “peculiar, high-pitched, irritating cry”. His co-authors, Mary Terrey and Elizabeth MacLachlan, provided the laboratory analyses and showed that this disorder, initially called “Dr. Lowe’s disease” in the medical records at the Massachusetts General Hospital. They showed also the indipendence both phenotypical and biochemical from historical forms of the renal Fanconi syndrome. Because of the three major organ systems involved (eyes, brain, and kidney), it is also known as OCRL (oculo-cerebro-renal) syndrome. In 1954, a renal Fanconi syndrome was recognised as being associated with the syndrome and, in 1965, a recessive X-linked pattern of inheritance was determined The gene has been mapped and the deficient enzyme has been identified, although its role is not fully understood.
Lowe's syndrome is a very rare disease. The prevalence in the general population si approximately 1 in 500,000. Lowe syndrome is a X-linked disease and for these reason patients affected are males in 99% of cases. According to the Lowe's Syndrome Association (LSA) in USA, the estimated prevalence is between 1 and 10 affected males in 1,000,000 inhabitants. The number of living in the year 2000 was 190 (0.67 × million inhabitants). The AISLO (Associazione Italiana Sindrome di Lowe) estimated that there were 34 Lowe's syndrome patients (33 boys and one girl) living in Italy in the year 2005 (0.63 × million inhabitants).
Lowe Syndrome, 2006
The carrier female is fenotipically normal. However, it is possible to determinte the carrier females with a specific ocular examination.
To determine the sensitivity and specificity of ocular examination for the carrier state of Lowe syndrome in females known to be either carriers or noncarriers by direct DNA analysis studied 31 females at risk for carrying Lowe syndrome in 3 families.
Slit-lamp biomicroscopy after pupillary dilation was performed by a single observer who was uninformed as to the carrier status of the women examined. Adult carrier women had small, irregularly-shaped, off-white lens'opacities. No false-positives were found among the 31 females examined. Only one false-negative was found in a 5-year-old girl.
Linkage studies in carriers of Lowe oculo-cerebro-renal syndrome, 1982
The mutation responsable of Lowe syndrome is the gene OCRL1 localized at Xq26.1, coding for the enzyme phosphatidylinositol bisphosphate 5 phosphatase, PtdIns (4,5)P2. This enzyme participates to inositol phosphate metabolism and phosphatidylinositol signaling system.
OCRL1 belongs to a sub-family defined by two domains structure. The two major conserved domains of these genes are a central inositol polyphosphate 5-phosphatase domain and a region towards the C-terminus with homology to the Rho GAP domain found in proteins that bind and stimulate the GTPase activity of Rho family small GTP-binding proteins.
OCRL1 is localized especially to the trans Golgi network. This spatial restriction may also be coupled to temporal regulation such that effectors are recruited not only to the correct membrane but also at the right time during a particular process.
The gene encoding human OCRL1 lies across 24 exons. Tissue-specific alternative splicing gives rise to two phosphatidylinositol bisphosphate 5 phosphatase's isoforms. This two isoforms are A and B.The difference, between A and B, is the presence or absence of an eight amino acid insertion.
Both forms are expressed in all tissues except brain, where the shorter isoforms is not present. In brain, only the longer form of OCRL1 is expressed. The significance of these differences is unclear at present, but interestingly, the alternatively spliced exon lies immediately adjacent to a clathrin-binding site (residues LIDLE). These means that the differences in clathrin association between the two forms may occur.
The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase
Accumulation of phosphatidylinositol (4,5) bisphosphate, PiP2, the main substrate for the mutated enzyme, in the Lowe cells lead to a disequilibrium of the phosphoinositides. This substances play a central role in
- cytoskeleton remodelling,
- in cell signalling and pathways of endocytosis.
In Lowe syndrome all process are altered and they are responsable of the abnormalities reported in affected patients.
The alteration of OCRL leads to a defective actin cytoskeleton polymerisation, a process that is essential in the formation, maintenance and proper function of tight junctions and adherens junctions. These junctions have been demonstrated to be critical in renal proximal tubule function and in the differentiation of the lens. In unaffected people, the modulation of PIP2 promotes actin assembly through a variety of effector proteins. One of this effector is N-WASP (neural Wiskott – Aldrich syndrome protein), which drives the assembly of Arp 2/3 complex.
The membrane traffic is deregulated because mutated PIP2 metabolism does not give birth to substance able to modulates the activity of the kinesin family motor Unc104, and the activity of effectors as dynamin 2, which is required for the formation of TGN-derived clathrin-coated vesicles, and Golgi spectrin, which has been implicated in regulating Golgi trafficking through the actin cytoskeleton.
In Lowe syndrome, infact, the cell signalling and the pathways that regulate endocytosis is abnormal. The phosphoinositide's disequilibrium at the plasma membrane obstruct clathrin-mediated endocytosis, making impossible recruiting a variety of clathrin accessory proteins to the membrane.
Lowe Syndrome Protein OCRL1 Supports Maturation of polarized epithetial cells, 2011
Mutations Are Not Uniformly Distributed throughout theOCRL1Gene in Lowe Syndrome Patients, 1999
The Deficiency of PIP2 5-Phosphatase in Lowe Syndrome Affects Actin Polymerization, 2002
Lowe syndrome is characterized by congenital cataracts, mental retardation and renal disease .It is not clear why the loss of OCRL1, a ubiquitously expressed protein, should result in defects to only the eyes, brain and kidney proximal tubule in Lowe syndrome patients. A possible explanation is that loss of OCRL1 is compensated in the unaffected tissues by another enzyme. The enzyme able to replace 5-phosphatase is Inpp5b, which shares more than 45% of his sequence with OCRL1 and has also a similar domain organization.
|Birth||Cataracts, hypotonia, corneal degradation, keloids|
|0-1 years||Fanconi syndome (kidneys) becomes apparent, loss of deep tendon reflexes (e.g. knee jerk), undescended testicle|
|3-4 years||Rickets may develop|
|0-10 years||Glaucoma may develop (50%), Febrile convulsions, Nystagmus/strabismus|
|>16||Joint swelling and arthritis, Development of scoliosis (50%)|
Symptoms related to the renal disease include:
- low molecular weight proteinuria, which appears to be present in all patients and may be helpful for perinatal diagnosis;
- proximal renal tubular acidosis;
- renal phosphate wasting, leading to the development of renal rickets, osteomalacia and pathological fractures;
- hypercalciuria, leading to nephrocalcinosis and nephrolithiasis as a result of the Fanconi syndrome;
- hypokaliemia, mostly related to secondary hyperaldosteronism
Defective protein readsorption in the proximal tubule is one of the major symptoms of Lowe syndrome and contributes to the development of kidney failure in patients. This process is mediated by the multiligand endocytic system composed by receptors megalin and cubilin. It is possible that megalin and/or cubilin function is perturbed in the Lowe syndrome proximal tubule. The level of megalin and cubulin in Low affected patient's urine compared with healthy subjects, is decreased. There is a loss of these proteins from the apical membrane. The traffic of megalin from the TGN to the cell surface is reduced and also the recycle from apical endosomes is slowed.
The recycle problem has been shown in a mouse model for Dent's disease. The kidney defects are similar to those of Lowe syndrome. Recently patients diagnosed with Dent's disease were found to have a mutation in OCRL1 and this is an evidence of the similarity of these two syndrome.
Dent's disease is typically due to a defective endosomal chloride channel, and this likely prevents recycling of megalin and cubilin by altering the endosomal pH. Whether the loss of OCRL1 also affects megalin and cubilin recycling to the apical membrane remains to be shown, but its localization to endosomes certainly puts it in the right place to regulate this process.
Dent-2 Disease:A Mild Variant of Lowe Syndrome, 2009
Dense cataract is present at birth in all patients. It develops in utero and is caused by altered migration of the crystalline embryonic epithelium. 50% of patients present glaucoma with or without buphthalmos. The glaucoma is detected within the first year of life and sometimes even later. Aphakia and retinal dysfunction compromise sight sharpness and are responsable of nystagmus. Corneal and conjunctival cheloids (present in 25% of patients) further compromise the sight
At birth is present a serious hypotonia and, often, there is the complete absence of the deep tendon reflex. These manifestations may compromise suction and cause serious respiratory problems in the first period of life. Motor development is retarded and the autonomous gait becomes apparent generally after the third year. About 10% of patients show slight mental retardation with an Intelligence Quotient (IQ) of 50 or less. Mental retardation has been attributed to defects in Rho GAP activity, but it is also possible that the high levels of lysosomal hydrolases in patients'serum cause tissue damage. OCRL1 appears to function in the clathrin-mediated delivery of lysosomal enzymes from the TGN to endosomes. In Lowe syndrome there are defects in this process and the lysosomal hydrolases rise up.
In the first period of life, numerous patients (87%) show evidence of conduct disturbance with irritability, outbursts of anger and non-finalised behaviour and auto or heteroaggressiveness. Obsessive-compulsive behaviour is typical. Approximately 50% of the patients over 18 years old have seizures and up to 9% of the patients present febrile convulsions. Cranial magnetic resonance imaging (MRI) may show a light ventriculomegaly. In 20% of cases is possibile seen also multiple periventricular cystic lesions.
Management and treatment
The alkali supplements are use to prevent acidosis which could damage renal tubular cells and aggravate the condition of the kidneys. These include citrates (sodium and/or potassium citrate) and sodium bicarbonate in variable doses and combinations, to maintain serum bicarbonate levels at around 20 mEq/l (doses may vary between 1–8 mEqKg/day, which should be divided into at least three separate doses).
In particular to reduce renal calcium excretion and to prevent nephrocalcinosis is usefull the Potassium citrate. If polyuria is present, patients should receive supplementary fluid. Sodium intake should be adjusted according to the extent of renal salt loss.
In infants and very young children, oral supplements should be promptly adjusted in case of diarrhoea. Intravenous infusions may be needed.
Rickets should be treated with oral phosphate supplements and vitamin D. During the treatment serum calcium and parathormone (PTH) levels should be maintained in normal range.
Currently, there is no evidence that increasing the dietary protein content above normal recommendations is of benefit for these patients. Similarly, there is no evidence that L-carnitine produces any improvement.
Cataract should be removed early. If is not possible the patient may develop amblyopia. It's possible also use eye glasses or contact lenses improves visual function and the psycho-social skills could be more increase than in a eye'problems patient. Glaucoma is easy to be diagnosed by test. Anti-glaucoma medication, or gonial or trabeculotomy surgery are good solutions in order to have a normal IOP. Conjunctival or corneal cheloids are difficult to treat. Surgical lens implantation is not recommended.
Rehabilitation therapy is necessary to treat hypotonia and its complications. Tube feeding is not necessary in the early stages of the disease. In order to prevent frequent and serious behavioural crises during adolescence is important that patients have an adequate psychological, pedagogical and occupational programme. The behavioural problems occurring during adolescence and the obsessive-compulsive disorder require specific competence on the part of the health staff.
Drugs such as neuroleptics, stimulants, benzodiazepines, anti-depressives (tricyclic antidepressants and serotonin reuptake inhibitors) although adequately prescribed, are only partially efficacious. More promising results appear to be found with clomipramine, paroxetine and risperidone.
Muscle and skeletal anomalies
Preventive treatments for the most common musculoskeletal complications are required to maintain articular mobility in order to avoid contractures. Osteopaenia and pathological fractures should be prevented by correct treatment of rickets. Standardised therapies (including the use of a corset and, if necessary, surgery) are required to prevent scoliosis.
Phosphoinositides undergo phosphorylation/dephosphorylation cycles through organelle-specific PI kinases and PI phosphatases that lead to distinct subcellular distributions of the individual PI species. Specific PIs control the correct timing and location of many trafficking events. Their ultimate mode of action is not always well defined, but it includes localized recruitment of transport machinery, allosteric regulation of PI-binding proteins and changes in the physical properties of the membrane. Now, is important to study these effectors and their work's way in order to intervene not only on Lowe syndrome, but in all those diseases that are characterized by an alteration in the regulation of phospholipid metabolism.
Lowe Syndrome, or Oculocerebrorenal Dystrophy (OCRL), has a recessive inheritance linked to X chromosome. It presents cataracts and glaucoma, delay in neuropsychomotor development, cognitive deficits, and renal Fanconi syndrome. 2010
Describe five patients with OCRL, attended at Tubulopathy outpatient clinic.
We performed a retrospective assessment of 5 male patient clinical charts of OCRL patients.
Mean age at first consultation was 76.5 and mean follow up interval was 30.5 months (8-53 months). Symptoms and clinical signs included cataracts and nystagmus. Neuropsychomotor development and weight and height deficits were present in whole cases, as well as polyuria, polydipsia, and intestinal constipation, metabolic acidosis, phosphaturia, bicarbonaturia, proteinuria, hypercalciuria, hyperuricosuria. Nephrocalcinosis was identified in one, renal lithiasis in three, and reduced kidney size in two patients. We found pathological fractures and rachitism in two, bone rarefaction and delay of bone age in all of the patients. One patient presented a reduction in the rhythm of glomerular filtration. Therapeutically, all patients received alkali, phosphorus and vitamin D reposition in addition to a dietary orientation adequate to their needs.