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educação diferente

Projecto da responsabilidade da apie - Associação Portuguesa de Investigação Educacional - Educação Especial e Deficiência.

educação diferente

Projecto da responsabilidade da apie - Associação Portuguesa de Investigação Educacional - Educação Especial e Deficiência.


Lowe Syndrome.  

Lowe syndrome is caused by a low activity of the enzyme inositol polyphosphate 5-phosphatase OCRL-1, which is encoded by the OCRL gene (chromosomal locus Xq26.1). Diagnosis may be confirmed by DNA tests or cultured skin fibroblasts demonstrating reduced (<10% of normal) activity of the enzyme. "Lowe Syndrome" is named after Doctors Lowe, Terrey, and MacLachlan who first described it in 1952 at the Massachusetts General Hospital in Boston. Because of the three major organ systems involved (eyes, brain, and kidney), it is also known as OCRL (Oculo-Cerebro-Renal) syndrome. The syndrome is apparent in all races, cultures and nationalities. The syndrome is caused by a DNA mutation - a single defective gene on the X-chromosome - that results in the lack of an enzyme. The mutation can occur without any family history (a spontaneous mutation) or may be inherited through the mother. Babies are born with bi-lateral cataracts, hypotomia (muscle weakness), kidney problems (wasting of essential nutrients) impaired growth, intellectual impairment and later may suffer brittle bones, arthritis, rickets, epilepsy (seizures) and behavior problems (autistic spectrum disorder). Many also have cysts and dental problems. 

The dental problems are often only apparent to a pediatric dentist having the patience, time and ability to closely examine the teeth of children with behaviour problems. See Caring for Lowe Children's Teeth. The diagnosis may be confirmed by testing for reduced levels of the OCRL enzyme in cultured skin fibroblasts or by a DNA test using a blood sample. As some DNA tests may not identify a mutation an enzyme test is the only conclusive test. See Baylor diagnostic flow chart (word.doc). See 2004 article by Great Ormond Street Hospital UK. entitled "Early proximal tubular dysfunction in Lowe's syndrome" Laube GF, Russell-Eggitt IM, van't Hoff WG.  Institute of Child Health and Great Ormond Street Hospital for Children, London, UK. The early diagnosis of Lowe's syndrome can be difficult. Urinary excretion of retinol binding protein (RBP) and the lysosomal enzyme  N-acetyl-glucosaminidase (NAG) were significantly increased in boys with Lowe's syndrome. Measurement of these urine parameters is recommended in suspected cases. Symptoms vary widely. Some boys are mildly affected and able to attend normal schools with special needs help, while others are severely affected with loss of sight and mobility. The medical and behaviour problems may require respite care or full-time residential care.  The NHS approach is of separate treatments of each clinical symptom, and family support by the local authorities through a special educational needs assessment (SEN). The "challenging behaviour" means that they frequently need to be handled in a playful manner, to prevent them from mischief. Parents, carers, teachers etc may need to be aware of UK laws on what is acceptable contact and on physical restraint. See article "Keeping Control". A complete description is available from the Lowe Syndrome Association USA booklet “Living with Lowe Syndrome”. A full medical description written by Dr Wappner of the LSA medical and scientific board is available at and searching for Lowe. Other descriptions are provided by and genetic databases NHGRI, The Genome Database, OMIN, Human Genome Mutation Database Cardiff. 

UK DNA testing for Lowe Syndrome may be requested from Dr A Wallace Email: awallace @ St Mary's Hospital Regional Genetics Services, Hathersage Road, Manchester M13 0JH. DNA and Biochemical tests and pre-natal testing is offered by Baylor College of Medicine USA. The following is one parents description of the syndrome: Boys are born with cataracts in both eyes and hypotomia (muscle weakness/floppy baby syndrome) and failure to thrive. The cataracts are usually removed at a few months old and the baby fitted with glasses and later contact lenses. Glaucoma occurs in some cases when older. Due to the weak muscles, there may be feeding (needing tube feeding) and digestion problems, and delayed development with crawling, standing and walking. Some parents say Growth Hormone greatly improved muscle development. After a year old, most boys develop kidney problems, with abnormal loss of substances in the urine, including bicarbonate, sodium, potassium, amino and organic acids, calcium, phosphate and L-carnitine. This is known as Fanconi-type renal tubular dysfunction. The losses may be mild to severe with large losses of many substances. Blood and urine tests are needed to establish the pH acidity and prescriptions needed to replace the lost substances. The kidney problems may also cause kidney stones and may be a factor for poor growth and small stature common with Lowe syndrome. Although not causing any medical problems, clusters of small cysts may become apparent on the skin around the sides of the waist. Cysts may also be shown by MRI scans to be present in the Brain. Lowe Boys have mild to severe mental impairment, delayed development and behaviour characterised as a autistic spectrum disorder .The behaviour includes temper tantrums, attention deficit disorder and obessive behaviour.  The degree of mental and behaviour impairment varies widely and does not seem to be related to the severity of the physical symptoms. Most children can speak and hold a conversation (by 5 -10 years old), read and even play computer games. Regular non-prescription hi-EPA fish and primrose oil capsules such as "eye-q" may help with mental and cartilage development. The boys have affectionate, happy and excited personalities with a cheeky sense of humor. When excited by a favorite subject many boys jump up and down with hand flapping and have obsessive behaviour with certain subjects such as videos or switches. Parents suffer from behaviour problems including stubbornness and severe temper tantrums (the famous Lowe Tantrum!) with periods of hyperactivity with inability to cooperate or control impulses. My son is aware of his behaviour and although unable to control it, will say sorry afterwards. Some also suffer from epileptic siezures that may become frequent and severe.    

Medical and Scientific Research

See  Spring 2007 On the Beam articles special research section<pdf>

Lowe syndrome is caused by a low activity of the enzyme inositol polyphosphate 5-phosphatase OCRL-1, which is encoded by the OCRL gene (chromosomal locus Xq26.1).  The sequence of biochemical steps that results in the disease remain unknown and there is no animal model of the disease. In the UK the first research was published in 1987 Manchester by Dr C McKeowm. "To estimate the prevalence and natural history of the condition in the British Isles Using Cytogenic and DNA techniques - to attempt to map the Lowe syndrome gene on the X chromosome" covering 26 boys and 1 girl. In 2004 there are now a number of research projects underway supported by the Trust. The first was a kidney research project using Lowe urine samples at Gt Ormond St/ICH. One of the objectives was to culture lowe cells from cells shed in urine samples and this has been successful. See 2004 paper "Early proximal tubular dysfunction in Lowe’s syndrome". A Dental survey has been carried out by Mike Harrison at Guys Dental Institute. In December 2002 an award of £50,000 over 3 years was made to the Department of Chemistry, Imperial College London to support a Phd studentship to research a chemical test for the OCRL enzyme. The research is entitled "Synthetic receptors for inositol phosphates: a novel diagnostic tool for the oculocerebrorenal syndrome of Lowe" by Dr Ramon Vilar-Compte and Dr Rudiger Woscholski. The project is being carried out by PhD student Marianna Mirabelli. See Imperial College Grant Award. In July 2003 a grant award £50,000 over 3 years was announced to University College London "Assessment of Golgi structure and membrane traffic in cells lacking P1 (4,5) phosphatase OCRL1" and to Dr John Lucocq of Dundee University "OCRL1 and its Lipid products - high resolution localisation and their role in membrane traffic and cell polarity". See Dundee University Grant Award. In 2003 Dr Martin Lowe at Manchester University started a 3 year research project entitled "Targeting of the phosphoinositide phosphatase OCRL1 to the golgi apparatus". See 2005 paper suggesting that megalin recycling may be deficient in cells lacking OCRL1 function and 2006 paper  "Membrane targeting and activation of the Lowe syndrome protein OCRL1 by rab GTPases"   We conclude that rabs play a dual role in regulation of OCRL1, firstly targeting it to the Golgi apparatus and endosomes, and secondly, directly stimulating the 5-phosphatase activity of OCRL1 after membrane recruitment. Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder that affects the brain, eyes and kidney proximal tubules. Lowe syndrome is caused by mutation of OCRL1, an inositol polyphosphate 5-phosphatase localised to the Golgi apparatus and endosomes. How loss of OCRL1 function brings about Lowe syndrome is poorly understood, but defects in membrane traffic are likely. To gain a better understanding of the molecular mechanisms underlying Lowe syndrome, we have undertaken experiments to identify novel OCRL1 interaction partners. This has resulted in the identification of a new Golgi-associated binding partner, termed p27. This protein is conserved in evolution and is expressed in all human tissues. The aim of the project is to characterise this protein in terms of its lipid binding characteristics, its interaction with OCRL1, and its in vivo function in cells. This will involve a variety of molecular cell biology techniques including animal cell culture, DNA cloning and PCR, immunofluorescence microscopy, protein biochemistry and cell based trafficking assays. The Gt Ormond St/ICH UK Kidney research is entitled “An investigation of intracellular metabolism in renal proximal tubular cells from patients with LOWE-Syndrome”. ICH project 02NU06 by Dr Robert Unwin, Dr Guido Laube and Dr William Vant Hoff.   “The proximal renal tubule is the major site of reabsorption of water, salts and minerals in the kidney. This involves heavy expenditure of energy and therefore the proximal tubule is sensitive to disorders affecting the energy supply to the kidney.  Despite the advances in our understanding and treatment of kidney diseases there are still unanswered questions. We and other groups have successfully isolated, cultured and characterized proximal tubular cells normally lost in the urine. It is possible using these cells in experiments to check the biochemical disturbances in the disease cells. Previous studies with this cell culture model have provided insight in the commonest and most severe genetic disorder of proximal tubular dysfunction, cystinosis. We are now investigating other disorders affecting the proximal tubule especially LOWE’s syndrome. We hope that the results will provide a better insight into proximal tubular function which will be relevant to healthy children and to those with renal and certain metabolic disorders. There is a possibility that defects in these pathways may be amenable to new therapeutic options”.

Com a colaboração: UK Lowe Syndrome Trust