Contributed by Dr

back Press release email: lowetrust @ homechoice.co.uk (+44) 208-458-6791

2004 International Lowe Syndrome Medical Symposium at the Royal Society London

Funded and organised by the charity, the first international conference on Lowe Syndrome was held on 2^nd December 2004 at The Royal Society in London, followed by a dinner at the RAC club. This historical event brought together over 50 international researchers, medical professionals and a parent to present and discuss the disease, current research underway and ideas for future projects.

The outcome of the discussions on the links between Dents disease and Lowe syndrome clearly indicated that clinical syndromes as they are described in the medical literature are not simply accounted by a single or multiple gene defects. See Press Release

The meeting was chaired by Prof. Robert Unwin UCL and was opened by Lord Turnberg, Scientific Advisor to the AMRC, followed by Prof. Nussbaum head of the cell biology division of the National Human Genome Research Institute in the United States. Robert discovered the Lowe's syndrome gene on the X-chromosome and has been instrumental in Lowe Syndrome research. Presenters included Dr. William van’t Hoff, Great Ormond Street Hospital, Marianna Mirabelli from Imperial College London, UK and Spain, Dr. Martin Lowe from Manchester University, Prof. Chris Oliver from Birmingham University, Prof. Steve Scheinman, Upstate Medical University, USA and Dr. Pedro Cutillas from the Ludwig Institute. Nationalities at the meeting included France (ASL), UK, USA (LSA), Spain, Germany and Italy (AISLO).

PROGRAMME

10:00 Welcome Lorraine Thomas, Chair, The Lowe Syndrome Trust

10:15 Introduction Lord Turnberg, Scientific Advisor to the AMRC

10:45 Lowe Syndrome an overview - Prof. Robert Nussbaum, National Institutes of Health, USA

12:05 Renal tubular dysfunction in Lowe Syndrome - Dr. William van’t Hoff, Great Ormond Street Hospital, UK

12:25 Synthetic receptors for inositol phosphates: a novel diagnostic tool for the oculocerebrorenal syndrome of Lowe - Marianna Mirabelli, Imperial College London, UK

12:45 OCRL1 and protein trafficking at the Golgi apparatus and endosomes - Dr. Martin Lowe, Manchester University, UK

2:15 Lowe Syndrome perspective from a parent - Fiona Fisher from Scotland.

2:30 OCRL1 and its lipid products - high-resolution localisation and their role in membrane traffic and cell polarity - Dr John Lucocq, Dundee University, UK

2:50 Behavioural phenotype of Lowe syndrome - Prof. Chris Oliver, Birmingham University, UK

3:30 OCRL1 mutation and the limited renal phenotype of Dent’s disease - a ‘link’ between Dent’s disease and Lowe syndrome? - Prof. Steve Scheinman, Upstate Medical University, USA

3:50 Potential insights from urinary proteomics in Dent’s disease and Lowe syndrome - Dr. Pedro Cutillas, Ludwig Institute, University College London, UK

4:05 Summing up and open discussion (led by Profs. Nussbaum, Kleta and Unwin)

Dinner at RAC Club Pall Mall

Abstracts

Robert Nussbaum - National Genome Research Institute USA Head of Inborn Errors and Cell Biology Section, Senior Investigator and Chief Genetic Disease Research Branch, Senior Investigator and Acting Chief Inherited Disease Research Branch
OCRL is a rare X-linked disease characterized by mental retardation, seizures, congenital cataracts and renal Fanconi syndrome. Our laboratory isolated the gene responsible for Lowe syndrome by positional cloning, and demonstrated that the gene encoded an enzyme, a phosphatidylinositol 4,5 bisphosphate 5-phosphatase. Fibroblasts from OCRL patients show a deficiency in this enzyme. Our subsequent work found that the enzyme is located primarily in the Golgi complex, particularly the trans-Golgi network. We are directing our current efforts towards understanding why a defect in this enzyme leads to the clinical signs of OCRL. This research relies heavily on cell biological and mouse genetics approaches, including transgenic and "knock-out" methods.

Synthetic receptors for inositol phosphates: a novel diagnostic tool for the oculocerebrorenal syndrome of Lowe

Marianna Mirabelli,^1,3 Joachim Steinke,¹ Ramon Vilar,³ Rudiger Woscholski^{2 ,} ¹Department of Chemistry, Imperial College London, London SW7 2AZ, UK , ²Department of Biological Sciences, Imperial College London, SW7 2AZ, UK , ³ICIQ – Institute of Chemical Research of Catalonia, 43007 Tarragona, SPAIN

The oculocerebrorenal syndrome of Lowe (OCRL) is caused by the loss of the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂] 5-phosphatase activity encoded by the ocrl1 gene. This loss of enzyme activity causes elevated levels of cellular PI(4,5)P₂ and this feature is indicative of the disease. The currently adopted diagnostic methods for Lowe syndrome rely on either the mapping of chromosomal DNA or biochemical assays of PI(4,5)P₂ activity; both of these techniques are expensive, time-consuming and cumbersome and are performed only in a limited number of places worldwide. In this project we aim to create a fast and reliable method for detecting PI(4,5)P₂ levels by designing a chemical receptor capable of selectively binding to the headgroup of this substrate. Such a receptor, if coupled to a chromophore or luminophore could in principle detect nanomol amounts of PI(4,5)P₂ and/or IP₃ and consequently it could be used as a diagnostic tool for OCRL.

The initial results towards the design and development of receptor molecules that can selectively recognise phosphorylated species will be presented. In particular a series of potential receptors incorporating hydrogen bonding functionalities have been prepared and their ability to bind mono- and bis-phosphorylated species evaluated using nuclear magnetic resonance (NMR) spectroscopy. One of the receptors has already demonstrated to bind selectively bis-phosphorylated species in preference to mono-phosphoesters.

Synopsis for Pedro Cutillas talk at the Lowe Syndrome symposium – 2 Dec 2004

Lowe syndrome and Dent’s disease are both forms of the renal Fanconi syndrome and these two groups of patients present similar kidney symptoms. Proteomic analyses of Dent’s disease urine indicated that the pathway defective in Dent’s disease has an important role in preventing urinary losses of vitamins and perhaps also in protecting the kidney from the bioactivity of plasma proteins. Therefore, a possible cause for the progressive loss of kidney function in Dent’s patients may be in an altered bioactivity of tubular fluid - i.e., the ‘pre-urine’ present in the lumen of kidney tubules - the composition of which is, at least in part, reflected in the final urine make-up. Extension of these studies to Lowe syndrome is currently in progress and preliminary data will be presented indicating that the protein composition of Lowe and Dent’s urines are similar; this may be interpreted as to indicate that the genes mutated in these two diseases are part of the same biochemical pathway. Conclusions obtained from studies on Dent’s disease may be extrapolated to Lowe syndrome and therapeutic strategies to treat and prevent kidney problems may be common for these two conditions.

OCRL1 mutations and the limited renal phenotype of Dent disease

Richard R Hoopes, Jr., Ph.D. 1, Antony Shrimpton, Ph.D. 1, Stephen J Knohl, M.D. 1, Paul Hueber, B.S. 1, Bernd Hoppe, M.D.* 2, Janos Matyus, M.D., Ph.D. 3, Ari Simckes, M.D.* 4, Velibor Tasik, M.D., Ph.D. 5, Berndt Toenshoff, M.D. 6, Sharon F. Suchy, Ph.D. 7, Julie Snoops, B.S. 7, Robert L. Nussbaum, M.D., Ph.D. 7 and Steven J. Scheinman, M.D.* 1. 1 Medicine, Upstate Medical University, Syracuse, NY, United States ; 2 Univ. of Cologne, Germany ; 3 Univ. of Debrecen, Hungary ; 4 Childrens Mercy Hosp, Kansas City, MO, United States ; 5 Clinic for Childrens Diseases, Skopje, Macedonia, The Former Yugoslav Republic of ; 6 Univ. Childrens Hosp, Heidelberg, Germany and 7 Genetic Diseases Research Branch, NHGRI, Bethesda, MD, United States

Bilateral congenital cataracts are considered the hallmark of Lowe syndrome, found universally in affected males and even present in carrier females and detectable prenatally. Dent disease is a renal tubulopathy in which the only abnormalities affect the kidney, with a renal Fanconi syndrome as in Lowe syndrome, but lacking acidosis. Dent disease is associated exclusively with mutations in the CLCN5 gene encoding a renal chloride channel.

In a study of 32 probands meeting strict phenotypic criteria for Dent disease, we found CLCN5 mutations in only 19. The renal disease in one family linked to Xq26.3 encompassing the OCRL1 gene. We found five previously undescribed mutations in OCRL1 among the 13 probands with Dent disease lacking CLCN5 mutation. PIP2 phosphatase activity was reduced in all 5, and Ocrl1 protein was reduced or undetectable by Western blotting, confirming the physiological significance of these mutations. Cataracts were absent by slit-lamp examination in all 5 probands, and none had acidosis. In one of these families the OCRL1 missense mutation segregated with the phenotype through 3 generations. These data establish that defects in OCRL1 are associated with broader phenotypic variability than previously appreciated, and in particular that such mutations are consistent with the absence of cataracts and a mild renal phenotype without acidosis or growth delay. They also suggest that other gene(s) may affect the severity of phenotype in patients with OCRL1 mutation.

Lowe syndrome and behaviour University of Birmigham Professor Chris Oliver Ms Joanna Mos, Ms Kate Arron, Ms Cheryl Burbridge, Ms Michelle Hooker, Ms Alex Caley, Mrs Lesley Wilkie & Ms Katy Berg

Although there has been significant research into Lowe Syndrome since the first description in 1952, most of these studies have focussed on genetics and medical symptoms associated with the syndrome. Very little research has addressed the issue of behaviour aI, emotional and cognitive profiles of people who have Lowe Syndrome. In a survey conducted by the Lowe Syndrome Association (McSpadden ,1991) it was shown that behaviour problems are common in boys with Lowe Syndrome. For example, 65% of 5 - 13 yr olds with LS showed self-

injurious behaviour (hits, scratches or bites self, or strikes body parts against hard surfaces) and 81 % showed stereotypic behaviours (twirls, rubs, shakes, or repetitively moves body parts or objects inappropriately) which are often associated with autistic spectrum disorders. Furthermore, it seems that in spite of all the medical complications associated with LS it is often the behavioural aspects that parents and carers find more difficult.

Two studies which have looked at behavioural aspects of Lowe Syndrome (Kenworthy, Park and Chamas 1993 and Kenworthy and Chamas 1995) support the LSA's finding that stereo typic and self-injurious behaviours are common. In the first study over 80% of boys were found to show a high level of problem behaviour (particularly "stubbornness", temper tantrums and stereotypic behaviours). In the second study, boys with LS were found to show significantly more problem behaviours than a group of controls who were the same age and had the same level of visual impairment and intellectual disability. The authors conclude that there is a specific pattern of behaviour associated with the diagnosis of Lowe Syndrome (as opposed to the behaviours being caused by the impairments and medical symptoms associated with Lowe, e.g. loss of sight).

In order to gain a more comprehensive understanding of the different types ofbehaviours associated with Lowe Syndrome we conducted a questionnaire study looking at six aspects of behaviour (challenging behaviour, repetitive behaviour, mood and interest, social communication, hyperactivity and adaptive behaviour). So far we have received data from sixteen participants (thanks to the UK Lowe Trust) and hope to gain more from a recent mail shot to members of the Lowe Syndrome Association of America. This study is being carried out as part of a larger study comparing behaviour across a number of different genetic syndromes. It will enable us not only to look at behaviour in boys with LS but also to compare the pattern of behaviours associated with LS to those associated with other syndromes. This should help us to identify behaviour which is particularly prevalent in Lowe Syndrome and begin to understand the causes of problem behaviour. The ultimate goal is to develop and evaluate interventions for the problem behaviour based on this understanding.

We are also working alongside the Learning Disability Service in Birmingham looking at the challenging behaviour shown by a young man with LS. We have observed this young man at school and are in the process of coding the behaviour seen using a computer programme developed for this purpose. Using this strategy we will be able to objectively document the behaviours he shows, the influence of the environment on these behaviours and the function these behaviours may serve. This work will enable us to advise and support the clinical psychology service with their intervention and will also further our understanding of the syndrome.