About Lowe Syndrome

Lowe Syndrome is a genetic disorder that can occur with no family history, affecting boys with multiple physical and mental handicaps including cataracts in both eyes, muscle weakness (hypotomia or floppy baby syndrome), kidney problems, cysts, brittle bones, arthritis, poor growth, mental impairment with behaviour problems (autistic spectrum disorder) and epilepsy. Lowe Syndrome has a wide spectrum of severity, and in milder cases shares similar genetic mutations with Dents Syndrome - a kidney disorder without the other Lowe symptoms such as cataracts.

 

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Lowe Syndrome in depth

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.

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.

 

Other descriptions are provided by eMedicine.com and genetic databases NHGRI, OMIN, Human Genome Mutation Database in Cardiff. 

 

UK DNA testing for Lowe Syndrome may be requested from Dr A Wallace Email: awallace @ smh5.cmht.nwest.nhs.uk 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.

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 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”.

France

In France the L'Association du Syndrome de Lowe is carrying out a Survey of Lowe patients organised by Dr Lunardi, and a DNA and/or biochemical diagnosis for Lowe Syndrome is offered at Biochimie de l'ADN,  38043 Grenoble. See request form format. Two research projects are supported by the Association: The first is by Dr Gérard Gacon and was published in July 2003 entitled "Lowe syndrome protein OCRL1 interacts with Rac GTPase in the trans-Golgi network". The second one is conducted in Dr Lunardi's lab and is entitled "Expression of the OCRL1 gene and phenotype-genotype correlations".

Italy 

In Italy there is the l'Associazione Italiana della Sindrome di Lowe. Dr De Matteis at the Department of Cell Biology at the Consorzio Mario Negri Sud is also researching the OCRL enzyme. A paper was published in may 2004 entitled "OCRL Mutation analysis in Italian patients with Lowe syndrome"

email: Maria Antonietta Melis (amelis@mcweb.unica.it)

*Correspondence to Maria Antonietta Melis, Dipartimento Scienze Biomediche e Biotecnologie, Via Jenner s/n, 09134 Cagliari, Italy. Click here for .pdf abstract.  "For the Golgi complex in particular, there is a vast array of phosphoinositide kinases and phosphatases, and the PPIs have been shown to play a role in membrane trafficking. Importantly, a defect in one of these PPI-metabolizing enzymes is responsible for a genetic syndrome affecting the eyes, brain and kidney (OCRL or Lowe Syndrome). Our aim is to: investigate how the activities of these PPI-metabolizing enzymes are regulated and co-ordinated at the Golgi complex, and how they regulate the function and possibly the structure of the Golgi complex; and determine what the targets of the different PPIs are, and whether the Golgi PPI-metabolizing enzymes serve a general role in the framework of inter-organelle or cell signalling".

 

USA

In September 2007 Yale researchers published a paper identifying a connection between a single gene mutation and the numerous symptoms of Lowe syndrome, a rare recessive genetic disorder. See Yale News and research paper. The main genetic research and coordination for Lowe Syndrome has been conducted in USA by a team lead by Robert Nussbaum who was Senior Investigator and chief of The National Human Genome Research Institute (NHGRI) in Washington USA. The team at NHGRI are: Robert Nussbaum, Sharon F. Suchy and Ti Lin who have created A Lowe Syndrome mutation database and a Lowe Mouse. In November 2002 Robert and Sharon published a paper on Lowe Syndrome and Actin Polymerization. In 2006 the Lowe Syndrome Trust awarded a grant of £50,000 to Professor Nussbaum MD, who is now at the  Institute for Human Genetics and Department of Medicine, University of California San Francisco.

“We isolated the gene for OCRL by positional cloning from a translocation breakpoint in a female with OCRL. We have shown that the OCRL gene is a phosphatidylinositol bisphosphate 5-phosphatase that is deficient in cells from Lowe Syndrome patients. The thrust of our research now is to determine how a defect in this enzymatic activity leads to the particular triad seen in the Lowe syndrome. As one important tool for studying OCRL, a mouse carrying a targeted knock-out of the OCRL gene has been constructed. Surprisingly, these mice show no signs of the disease. There are other genes in the human and mouse genome with strongly conserved domains that we believe encode phosphatidylinositol bisphosphate 5-phosphatases. The current hypothesis in the lab is that one or more of these genes may be compensating for the lack of OCRL activity in mice, but not in humans. We are investigating this possibility by making mice deficient in these other genes as well and then crossing them to create double knock-outs as a genetic screen for functional overlap. More broadly, embryonal stem cell technology is a powerful tool for analyzing and dissecting other signal transduction pathways, including the inositol signaling pathway”.

Kidney transplants on Lowe Syndrome patients have been carried out at Alabama Childrens Hospital by Mike R Benfield MD: Email mbenfield@peds.uab.edu  

 

In 2001 the UK Lowe Syndrome Trust contributed funds to the Lowe Syndrome Association USA to help fund two research projects in USA. One is at the Thorner Laboratory, University of California and the other is at The Jorgensen Laboratory at the University Of Utah.

The project at the Thorner Laboratory is entitled "Phosphatidylinositol 4-Kinase, Pik1, Shuttles Between the Nucleus and the Cytosol:  Exploring the Physological Function of  PtdIns(4)P Generation in the Nucleus"  by Prof. Jeremy W Thorner, Professor of Biochemistry & Molecular Biology Division of Biochemistry,. The studies are being carried largely by a senior postdoctoral research fellow, Thomas Strahl (Ph.D., University of Freiburg). Professor Thorner has recently had an article published by the journal of biochemical Chemistry entitled "Molecular interactions of yeast frequenin (Frq1) with the phosphatidylinosotol 4-kinase isoform Pik1".

 

 “Phosphatidylinositol 4,5-bisphosphate, abbreviated PtdIns[4,5]P2, is a component of cellular membranes. PtdIns[4,5]P2 has been implicated in many physiological  processes, including:  as the precursor to several cell signaling molecules (dubbed second messengers);  as a molecular determinant that is recognized by the proteins that must be recruited to membranes to carry out various kinds of vesicular transport;  and, as a regulator of several classes of proteins that control the state of assembly of actin microfilaments, essential  components of the architectural framework (cytoskeleton) of the cell, which are often intimately associated with membranes and membrane dynamics. 

The level of PtdIns[4,5]P2 in any given membrane is dictated by the balance between its rate of synthesis and its rate of breakdown.  PtdIns[4,5]P2 is generated from PtdIns[4]P by enzymes called PtdIns[4]P 5-kinases.  By contrast, the job of the enzyme missing in patients suffering from Lowe Syndrome—  a Golgi-localized PtdIns[4,5]P2 5-phosphatase (product of the OCRL gene)  —is to convert PtdIns[4,5]P2 back into PtdIns[4]P.  Hence, the pathological manifestations observed in Lowe Syndrome presumably reflect problems caused by over-accumulation of PtdIns[4,5]P2, and/or a paucity of PtdIns[4]P, in some critical membrane compartment(s), presumably the Golgi.

If the problem is over-accumulation of PtdIns[4,5]P2 (and not a deficiency of PtdIns[4]P), one potential way to prevent over-accumulation of PtdIns[4,5]P2 would be to identify a means to reduce the rate of synthesis of its immediate precursor, PtdIns[4]P, and to do so in the correct subcellular compartment.  PtdIns[4]P is generated from PtdIns by a class of enzymes, called PtdIns 4-kinases, which are found in all eukaryotic organisms examined to date.  This evolutionary conservation extends from unicellular microbes, like yeast, to humans.  There are two related isoforms of this type of enzyme, called alpha and beta;  in the budding yeast, Saccharomyces cerevisiae, these are encoded by the STT4 and PIK1 genes, respectively.  Both enzymes are essential for the viability of yeast cells, and neither enzyme can substitute for the other, suggesting that these enzymes generate intracellular pools of PtdIns[4]P that are not interchangeable.  Indeed, Stt4 seems to perform its function at the endoplasmic reticulum and plasma membrane, whereas we have found that Pik1 shuttles between the nucleus and the cytoplasm and, in the cytoplasm, localizes primarily to the Golgi apparatus.  The PtdIns[4,5]P2 5-phosphatase that is defective in Lowe Syndrome patients is also localized to the Golgi.  If we could devise a means to retain more Pik1 (and, by extension, its mammalian counterpart) to the nucleus, thereby reducing the amount of Pik1 at the Golgi, this approach might provide a means to reduce PtdIns[4]P generation and hence PtdIns[4,5]P2 accumulation in the Golgi compartment.  This strategy might eventually provide an approach for early intervention that could help ameliorate some of the symptoms in patients diagnosed with Lowe Syndrome”.

The project at the Jorgensen Laboratory is entitled “Genetic Suppressors of 5-Phosphotase Mutants in C.Elegans" by Erik M.Jorgensen, Ph.D, Kimberley and R. Schuske Ph.D in the department of Biology at the University of Utah in Salt Lake City USA. In November 2003 a paper was published with acknowledgment to the trust entitled  "Endophilin Is Required for Synaptic Vesicle Endocytosis by Localizing Synaptojanin"

“Individuals with Lowe Syndrome lack an enzyme called OCRL and because of this an activating signal called PIP2 accumulates in their cells. The accumulation of PIP2 causes the behavioral and physical disabilities suffered by individuals with this disease. In our research we use a model organism Caenorhabditis elegans, which is a small nematode worm. We have characterized a worm strain that is defective for a similar enzyme to OCRL called synaptojanin. The synaptojanin protein has the same substrate as OCRL, and animals lacking synaptojanin accumulate PIP2, similar to Lowe syndrome individuals. Worms that lack synaptojanin function do not move as well as worms that have the protein. Our research involves exposing synaptojanin deficient worms to a mutagen in order to disrupt genes. We then screen for animals that move better then the synaptojanin deficient worms. By taking this approach, we hope to identify proteins that, when inhibited, will reduce the amount of PIP2 in worms that have high levels of this signaling molecule. If such a protein is identified, it may eventually be a target for drug intervention experiments”.  

Other researchers that have been supported by the Lowe Syndrome Association USA are as follows:  

 

Blazer-Yost, Bonnie, Ph.D.  Email: bblazer@iupui.edu. In Sept 2001, Bonnie hosted a lab tour for lowe families at the end of the 200-mile fundraising walk by Anne Keefer. In a research project funded by a two-year grant from the LSA, The professor and graduate student, Annique Wilson, are searching for answers among the chemical reactions within individual kidney cells. The goal is to understand the normal function of what is called the oculo-cerebro-renal syndrome of Lowe (OCRL) protein in order to determine what happens when the protein is absent. The researchers are tracking fluorescent-tagged normal and abnormal proteins as they make their way through biochemical pathways within kidney cells grown in tissue culture By observing the processes within the individual cells, the researchers hope to determine how Lowe Syndrome causes malfunctions within other body organs. Research papers: 2000 Stable Expression of the OCRL1 Gene in Renal Epithelial Cells: Models for Studying the Localization, Regulation and metabolic Role of the OCRL1 Protein. 1999: The Phosphoinositide Pathway in Regulation of Ion Transport Phenomena in a Renal Distal Tubule Cell Line. 

Richard A. Lewis, M.D developed tests for Lowe Syndrome at Baylor College of Medicine. Research papers: Refined gene mapping, carrier detection, and prenatal diagnosis of the Oculo-Cerebro-Renal Syndrome of Lowe,  Baylor College of Medicine offers a Prenatal diagnosis for Lowe syndrome can be performed on cultured amniocytes or chorionic villus cells. Baylor  also offers DNA and Fibroblast testing service for Lowe Syndrome. To make arrangements for any of these tests, physicians should E-mail: dnalab@bcm.tmc.edu and see web links for DNA Form. A DNA test costs  $1900 US.