Conference 2004 Abstracts

Authors/Presenters

Abstract Description

Barbara Hopwood

Co-ordinator Lifestyle Rehabilitation

ACH Group, Inc.

Getting the Most from Services

A wide range of services is available to families which complement primary medical care given by specialist and general practitioners.

Unfortunately, these services vary from state to state in Australia and within local areas. So how do families find the resources that they need? Who can best assist families to make the choices that suit them?

In the first instance it is the medical specialist who will be involved in counselling the family following initial diagnosis and who will oversee the ongoing medical treatment. In most Australian states there is a medical specialist who is expert in the management of MPS diseases and who has a support team of allied health professionals able to assist families. In particular, social workers and genetic counsellors are trained to help families make choices about services which would suit their particular circumstances.

It is imperative that during the MPS journey families are able to access the services that they need. Needs change over time and it is so helpful to have a support person who can help families by providing information, and ensuring that assistance is forthcoming.

The role of the family associations and support groups is crucial in this respect, sharing information and support can help families stay in control of their own particular situation.

There are specific services available including those provided by hospital social workers and genetic counsellors; income support, social work services, disability officer services for employment for young adults with MPS and mobility allowance from Centrelink; respite through Carers Support and Respite Services; Home and Community Care Services (HACC) which include home and personal support in the home usually organized through various local agencies including local government councils; equipment from various sources.

Many family associations, support groups and services have websites which are also useful and access to the internet is available through local libraries, and community houses.

Preimplantation Genetic Diagnosis: A New Option For Couples

Preimplantation genetic diagnosis (PGD) and assisted conception is a new reproductive choice for couples at risk of having a child with a serious genetic condition. This technology provides the couple with an opportunity to commence a pregnancy knowing that their child will be not be affected. PGD involves testing of biopsied cells from the couple’s embryos for the indicated genetic condition and the transfer of one or two unaffected embryos back to the women’s uterus to establish pregnancy. The most common indications for PGD are Cystic Fibrosis, Huntington’s disease and X-linked conditions. So far, Monash IVF have performed 81 PGD cycles, resulting in the birth of 15 healthy babies and 2 ongoing pregnancies. PGD is available for almost any genetic condition, including mucopolysaccharide and related diseases, where prior DNA testing has been performed on both partners to identify the causative genetic lesion.

Obstructive Sleep Apnoea (OSA) is a medical condition where there are repeated obstructions to breathing when the child is asleep. This can result in poor sleep quality and low oxygen levels during the night which can lead to impaired daytime performance, daytime sleepiness, poor growth and in severe cases heart failure. In most children OSA is caused by large tonsils and/or adenoids. Children with MPS are at increased risk for OSA because of deposition of glycosaminoglycans in the soft tissues in the upper respiratory tract, and associated skeletal abnormalities. History and examination can be suggestive of OSA but definitive diagnosis often requires a sleep study. Performing a sleep study in young children or those with disabilities can be a challenge and requires specialized equipment and experienced staff. Management of OSA includes adenotonsillectomy, continuous positive airway pressure (CPAP), or tracheostomy.

The mucopolysaccharidoses (MPS) are a group of inherited disorders which were first recognised by astute clinicians and the disorders which they described bear their names. MPS disorders result from a functional deficiency of an enzyme which is a special type of protein. These enzymes are responsible for the recycling of large compounds called glycosaminoglycans (GAGs) (previously called mucopolysaccharides) and the enzyme deficiencies result in the accumulation of GAGs within the cells and tissues. Within each MPS disorder, the specific enzyme can be affected to varying degrees, from a mild reduction in function to total absence. This results in varying degrees of severity within each MPS disorder, from mild to severe. Each of the enzymes is coded for by a pair of genes and the type of alteration (mutation) in the gene determines the severity of the enzyme deficiency. All of the enzymes involved in MPS disorders are usually active within a special compartment of the cell which is called the lysosome. The MPS disorders are part of a group of greater than 40 disorders which result from abnormal function of enzymes in the lysosome and collectively they are called Lysosomal Storage Diseases (LSD). The mucolipidoses are also LSDs. Australian scientists have played a leading role in the discovery of the enzymes and genes in MPS disorders and in understanding their function.

The diagnosis of MPS is the beginning of a journey , that many families are unprepared for and do not want to make. Each family member , including parents, siblings, grandparents, friends, will be affected , often in different ways and each may deal with the diagnosis in different ways. Parents and their families experience a range of emotions from shock, disbelief, fear, and anger. Information is vital, but can be overwhelming , and parents who are upset may not hear information. Clear communication between families and health professionals is important , to build a trusting relationship that enables parents to ask questions that are important to further their understanding of MPS and the implications for their family. Other families who have a child with MPS, and the MPS Society, are important in this understanding and support, but some families do not initially want to have contact. Tolerance and a recognition of the individualised needs of each person, is important for health professionals and the MPS Society. Strategies for families at this time of diagnosis are discussed.

This paper will focus on general aspects of hydrocephalus and CSF diversion in MPS patients. In particular, it will detail the surgical techniques employed in insertion of a shunt, possible complications from shunt procedures and what to look for in the event of a shunt malfunction in the future, as well as the management of shunt malfunction. Furthermore, as MPS kids have quite specific needs and clinical issues, shunt malfunctions may present in ways different from shunt malfunction in children with obstructive hydrocephalus.

Carpal Tunnel Syndrome is a well known complication with mucopolysaccharidoses. The cause of this is unclear, but it is thought to be due to deposition of mucopolysaccharide within the carpal tunnel. The carpal tunnel is a tunnel which contains nine tendons at the level of the wrist, also contains the median nerve. The initial symptoms of this are tingling within the fingers, particularly the thumb, index, middle and ring fingers, which usually occurs at night. As the syndrome progresses there is increasing numbness within the fingers which can become permanent. It can also produce altered sensations with pins and needles and shooting pains in the hand. Commonly there is associated pain at the wrist and if not treated wasting and weakness can occur within the muscles of the thumb. Current feeling with carpal tunnel syndrome is that if it is diagnosed then this should be treated in these children with mucopolysaccharidoses. This is because of the associated flexion deformities these children may develop in their hands, one should remove any possible contributing factors that may diminish hand function.

The Facilitators will explore the changing faces of grief as reflected in the stories of loss, change and hope families bring. Drawing from their experiences of working with families Mandy and Virginia will provide a forum where the impact of grief will be acknowledged and strategies for living with grief and facing the future will be shared.

People with MPS and related disorders, like people in general, go through life phases. We are facing a new phenomenon, which probably has always been there. Improvements in general health and all-round medical care mean that the “later” years in MPS are as important to know about as the early years. More and more adults are recognized with attenuated forms of MPS and Oligosaccharidoses (OSD). Recently adults with Sanfilippo type MPS were diagnosed in their 50’s. Older people with all types of MPS living into the fifth and sixth decade have a prolonged period of slow deterioration in health, arthritis, heart failure or neurological symptoms. For most people with MPS, the later years are late childhood (10-14 years) and teenage years. However later years may even start in the 20’s or 30’s.There is such a wide range of situations it is not possible to generalize. However some themes include gradual visual loss in MPS III and MPS I, progressive respiratory failure in MPS II, progressive spinal cord impairment in some people with MPS IV and MPS VI and progressive joint problems in MPS VI. We will discuss approaches to regular assessment, “routine care” and specialist medical care for parents and people living with MPS. Getting around (mobility), getting showered and dressed, eating and feeding raise many issues. We know however that positive problem solving vastly reduced the stress on affected people and their carers.

Pre-implantation Genetic Diagnosis (PGD) has developed to become a real option for many families who risk passing a particular genetic condition to their children. Although there is little written about the impact of PGD on families, practice experience can help us to understand what this impact can be. The physical impact of PGD involves IVF treatment which many find invasive. The emotional and psychological impacts of PGD include a wide range of issues, such as, feeling the need to have PGD due to a huge sense of responsibility towards a future child; the emotional roller-coaster of waiting for results at various points in the IVF process; and the possibility of entering a pregnancy with less fear and anxiety. The ethical and social impact of PGD may involve a decision to dispose of affected embryos; and questions of whether to tell other family members about a decision to embark on PGD. There is also a financial impact of PGD. Both the positive and challenging impacts of PGD on families will be discussed.

Stress is a part of life. Like most other aspects of living, it has its positives and negatives. Negative stress if it is prolonged, can affect a person at all levels – mind, body, spirit, sometimes resulting in ill-health. This presentation will explore some ways in which care giving stresses can be reduced and quality of life improved and health and wellbeing enhanced. The focus will be on self-awareness and choice – and a range of strategies that can be used.

Recent advances to achieve effective therapies for lysosomal storage disorder (LSD) patients will be reviewed. Since the 9th National MPS Conference in Canberra there has seen considerable expansion in the accepted clinical use of enzyme replacement therapy (ERT) for the treatment of a number of LSD types. ERT for Gaucher has now been in clinical use for over ten years. Importantly, during the past few years ERT has been approved as a therapy for Fabry and some mucopolysaccharidosis (MPS) type I patients, and is under clinical trial to investigate its efficacy for Pompe, MPS type-II, -VI patients. Clinical trials are planned to assess the efficacy of ERT in MPS IVA and Niemann-Pick type B patients. We therefore anticipate that over the next few years, ERT will become an approved therapy for many LSD patients. At present, ERT is unlikely to prevent the development of pathology in the brain of LSD patients. However, bone marrow transplantation (BMT) has been shown to be an effective therapy to reduce brain pathology in some LSD patient types. For example, MPS I patients that go on to develop the extremely severe Hurler type respond to BMT if the transplant is placed early. Combined ERT and BMT are under evaluation in MPS I patients who develop with the extremely severe Hurler type.

With the advances in technology and the possibility of future treatment, families are faced with decisions about their participation in trials that offer hope for their child’s future. With this hope comes uncertainties, and issues for families and professionals and our society. These issues need to be openly considered and discussed to ensure that families are aware and best prepared to deal with them. Each family will have a different perspective, and issues will be raised to encourage discussion, reflection and sharing of experiences. This presentation focuses on issues raised by families and professionals with whom the presenter has contact as a social worker at Genetic Health Services Victoria, and through her contact with families in MPS Australia and other support groups.

Enzyme replacement therapy (ERT) holds tremendous potential in the management of both children and adults with MPS and related disorders. The therapy is very expensive and funding from Government is not guaranteed. Although as a percentage of the Health Budget the costs are small, as a cost per individual they are amongst the most expensive forms of therapy available. There are many competing programmes for the governments’ funds and most of these have the advantage of being one off treatments rather than recurrent therapies as is the case for ERT. In the fields of genetics and metabolic medicine, most of the tests and therapies attract no government subsidy. The monies available for health care is not unlimited and some influential individuals have questioned the benefit to the community of paying large amounts for the care of an individual when the same funds could be used to provide another treatment to several individuals. A number of recent events have demonstrated the power of the affected individual or their family in convincing government of the need to fund specific projects. These therapies are funded in countries with similar health systems, such as Europe, and this is an important consideration for our governments. Whether or not these therapies are funded will depend heavily on your efforts in lobbying appropriate politicians.

Mucopolysaccharidosis type VI is due to lack of the enzyme N-acetylgalactosamine-4-sulfatase (ASB). Trials of enzyme replacement therapy with recombinant human ASB (rhASB) are currently in progress. Results have been encouraging to date with the rhASB being well tolerated and significant improvements in many measures of patients’ health, particularly endurance. Results of the phase 2 trial up to week 48 show significant and continuing improvement in endurance as measured by a walk test and stair climb. Biochemical improvement is also show by marked reduction in urinary glycosaminoglycan excretion in all patients treated in this trial.

The talk will give an overview of the traditional management of Hurler Syndrome by BMT, focusing on the advantages and limitations. It will discuss the role of Enzyme Replacement Therapy alone in the management of MPS 1. It will discuss the role of ERT in augmenting the benefits of BMT in the management of Hurler Syndrome, including its limitations.

Twenty five patients with ML II and III were ascertained from clinical genetics units in Australia and New Zealand and National Lysosomal Diseases Research Unit in Adelaide (ANZ Mucolipidosis Consortium). A core set of data focussing on biochemical parameters at diagnosis and radiographic findings at various ages was sought for each patient. In people who could be examined, we performed a skeletal survey, bone densitometry, and measurement of serum and urine markers of bone metabolism. Functional assessment was performed using the Paediatric Evaluation and Disability Inventory (PEDI). Metabolic bone investigation in ML II confirmed that all patients had secondary hyperparathyroidism. In ML III, there was normal serum calcium and phosphate but mild elevation of alkaline phosphatase. Serum osteocalcin and deoxypyridinoline/creatinine ratios were elevated. Bone densities measured by Lunar DXA were low in the spine in all patients. Radiographic analysis confirmed that ML is characterised by an osteodystrophy which is manifest as two clinical syndromes. There is an acute transient hyperparathyroidism lasting until 3 to 4 months of age in ML II which evolves into a slowly progressive and destructive bone disorder typical of osteitis fibrosa cystica with normal serum parathormone which is also present in ML III. In both ML II and III, this resulted in painful joint destruction and spine deformity. Cyclic Intravenous Pamidronate (CIP) given as a monthly intravenous regimen in 8 subjects (ML II;1, II/III;4, III;3) for over 12 months stabilised and reversed the destructive bone disease and lead to increase mobility and vast improvement in quality of life. The actual total BMD score was statistically significant (p<0.05) although the increments were modest compare to children receiving CIP for the treatment of osteoporosis in osteogenesis imperfecta. In four patients who underwent serial joint range of motion assessments, there was demonstrable improvement.  There was loss of bone pain after 6 months. All patients became more active and all parents perceived improved patient quality of life during the treatment period. We observed variability in response between groups of patients which raised the possibility that there were differences in response depending on underlying molecular basis for the disorder (3 complementation groups are known). Conclusion: Mucolipidosis II and III are associated with chronic progressive “metabolic bone disease” or osteodystrophy. Treatment with a low dose cyclic regimen of intravenous Pamidronate arrested and partially corrected the osteodystrophy associated with mucolipidosis resulting from phosphotransferase deficiency disorders.

Adelaide is one of 6 world-wide sites looking at the natural history of Hunter syndrome in a study sponsored by TKT. The study goes for 2 years and we are now half way through. 18 men and boys with Hunter syndrome, together with their families came from all over Australia to tell their stories and to share how Hunter syndrome affects their lives.

As we enter the twenty first century, more must be done to ensure that adolescents and adults with Mucopolysaccharidoses and related disorders (MPS) have access to comprehensive management including assessment, medical treatment, rehabilitation and information about their disorder. In our centre, we provide such a service for children (Connective Tissue Dysplasia Clinic). While individualised for each child, the service otherwise involves the same core management offered to every child, ie there is a protocol and the same core personnel. Why doesn’t this happen for adults? Basically, services for adults are either not provided on a multidisciplinary basis, or adults must access a large number of linked speciality services, which are neither integrated nor coordinated. Hence the central objective for adolescents and adults with MPS is to link in with a family doctor, general physician or rehabilitation specialist (or generalist) who is willing to co-ordinate care and can be educated about the MPS disorders and their individual problems. The doctor will need to go on learning about the disorder during this time. Childhood represents a fifth of life. So this ’generalist’ may need to co-ordinate and orchestrate care for four-fifths of the life-span of a person with MPS; during adolescence, young adult life, post menopausal/early-aging period through to late aging. There are two broad categories of management themes, (i) continuous threads, (ii) age-specific management issues. Even people with mild MPS have numerous challenges with activities of daily living (ADL). The age independent management issues include joint limitation, progressive musculo-skeletal impairment, accessibility in the workplace and home adaptation. Reproductive Issues: Adolescents and adults with MPS ask about what will happen if they have children. For Autosomal Recessive Disorders (all the MPS except Hunter), all the children of an affected person will be carriers of one gene for their disorder ie. normal carriers but the children will not be affected. Similarly all the daughters of Hunter males will be carriers but the sons neither affected nor carriers. In general pregnancy is contraindicated in women with any type of MPS because of the. Abstracts - Saturday risk of respiratory failure and deterioration in health during a pregnancy Disorder Specific and Age Specific Issues: Heart The heart valves become thickened and stiff in most adults with MPS. This inevitably results in a leak of blood across the valves and this type of leak is called ‘Incompetence’, that is Mitral Incompetence or Aortic Incompetence. The heart can now be simply monitored by imaging with ultrasound, a technique called Echocardiography. A cardiologist checks the heart and evaluates the ECHO and will prescribe specific treatment. Hunter men have special problems with their heart. Carpal Tunnel Syndrome This refers to the tendency of the nerves in the wrist to be compressed by a build up of tissue deep in the space between the ligaments at the wrist. The symptoms are numbness and tingling or pain in the wrist or fingers. A special type of operation is required to release the compression, not just at the wrist but also where the nerves enter the fingers. Sleep Apnea Nearly everyone with MPS will develop Sleep Apnea, that is, pauses in breathing during sleep. It is sometimes called OSA (Obstructive Sleep Apnea), however it has both an external obstructive component from a large tongue and an internal component due to pressure on the base of the brain. The treatment involves using a face mask at night with a small machine which delivers positive pressure to the upper airway. This produces a surprisingly good night’s sleep and a clearer head the next day. Its medical benefit is considerable as it relieves the stress on the heart and lungs. Specific Therapies Bone marrow transplantation (BMT) has usually been employed with MPS when the children are young. Thus some adults have BMT modified MPS i.e. they still have MPS but its features have been changed by the bone marrow transplant. Enzyme Replacement therapy (ERT) with purified enzyme preparations are being trialled for several MPS disorders at present. It is hoped that when trials are conducted in the future it will be possible to include some adults with MPS in those trials as it is likely that enzyme replacement therapy will improve the quality of life for those adults. However it may be difficult for any therapy to prevent progress of the musculo-skeletal problems and heart problems in adults with MPS.

In the development of new treatments for complex disorders clinical trials are an essential part of the process. Selection for trials can be a source of frustration or hope depending on the role and view of the person and people involved. New treatment development begins with basic research then progresses to trials, marketing, further research and follow-up. At each step there are different requirements and goals, sometimes conflicting so that the process can seem arbitrary or unfair. To understand this it is important to understand the differing needs of all those involved so that the ultimate aim of safe effective, available treatment is achieved.

This review will present the latest information about research studies to advance diagnostics and treatments for lysosomal storage disorder (LSD) patients. The successful introduction of enzyme replacement therapy for LSD patients, who are free of brain pathology, has accelerated research effort to develop effective therapies for the many LSD patients who do go on to develop brain pathology. Specific examples of these LSD types include Sanfilippo, Hurler and early onset Hunter diseases. A number of therapy types under research to evaluate their ability to prevent brain pathology include various modifications and combinations of bone marrow/cord blood transplantation, stem cell transplantation, enzyme replacement therapy and gene replacement therapy. Naturally occurring animal models for a number of different LSD types have enabled this research to proceed rapidly. All therapies, particularly for those LSD involving bone and/or brain, would benefit from diagnosis and commencement of therapy before the onset of irreversible pathology. Research is well advanced to develop methods to diagnose presymptomatic LSD patients together with an ability to predict clinical severity in the newborn period.

A report of recent activities to establish Global Organization for Lysosomal Diseases (GOLD) will be presented. GOLD is an international collaborative effort initiated in 2002 to improve the lives of all lysosomal storage disorders (LSD) patients. GOLD priorities and programs are to be determined by an alliance of researchers, clinicians, patient advocacy groups and industrial partners. GOLD is currently directed by a Steering Group [comprising Michael Beck, John Hopwood, Ed Kolodny, Christine Lavery, Abbey Meyers and Bill Sly], has a web site [www.goldinfo.org], has just registered with the Charity Commission of England & Wales [Registered Charity No: 1102478 46] and appointed Dr Ann Hale as Executive Director [Woodside Road, Amersham Buckinghamshire, HP6 6AJ; Ann.Hale@Goldinfo.org].

PO Box 623, Hornsby NSW 1630, Ph (02) 9476 8411, Fax (02) 9476 8422, Email info@mpssociety.org.au