The concept of evidence-based medicine stipulates that the efficacy of any therapy must be shown in large clinical studies before being used for treating patients. However, this is a requirement that cannot be realistically fulfilled for rare diseases due to the small number of people affected. To redress this situation in the case of leukodystrophies, rare metabolic disorders of the nervous system that affect only a small number of people in Germany, the German Federal Ministry of Education and Research is funding the German expert network LEUKONET. The network encompasses ten projects, with clinical research being coordinated by Prof. Dr. med. Ingeborg Krägeloh-Mann from the University Children's Hospital in Tübingen and Prof. Volkmar Gieselmann, a basic scientist from the University of Bonn.
In the concept of evidence-based medicine, randomised controlled studies are the gold standard for assessing the efficacy of new medications and therapies. However, studies involving large numbers of patients cannot be carried out to assess treatment options for rare diseases because there are too few patients to enable a reliable statistical evaluation of the findings. This is the case of leukodystrophies, a group of genetic metabolic disorders characterised by the progressive degeneration of the white matter (myelin) of the brain and spinal cord. Only around 2,000 people in Germany suffer from this particular disease.
"MRI (magnetic resonance imaging) is the primary imaging modality for detecting white-matter abnormalities in patients suffering from leukodystrophies," said Prof. Dr. med. Ingeborg Krägeloh-Mann, medical director of the Department of Neuropaediatrics at the University Children's Hospital in Tübingen. The aetiopathology of the different types of leukodystrophies differs considerably. "In leukodystrophy, symptoms gradually worsen over time, and start with the loss of already acquired motor abilities. This is particularly the case when the disease occurs during early childhood," said the paediatrician. For example, children who are already able to walk suddenly either find it difficult to walk or lose the ability completely. Over time, the children also develop considerable impairments in cognitive functions, including impaired vision, speech disorders and attention deficits. Children suffering from leukodystrophies often die at a very young age.
The LEUKONET network was established in Germany in 2002 to systematically investigate leukodystrophies characterised by the progressive degeneration of myelin. Although funding from the German Federal Ministry of Education and Research (BMBF) will come to an end in 2011, "we will continue our work under the LEUKOTREAT project, a new EU-funded project," said Prof. Dr. med. Ingeborg Krägeloh-Mann.
Figures on metochromatic leukodystrophy (MLD) clearly highlight the importance of acquiring patient data on a national, and if possible, international level. MLD is a very rare type of leukodystrophy caused by a mutation of the gene encoding the enzyme arylsulfatase A. "Before we started LEUKONET in 2002, we saw no more than one MLD patient a year in Tübingen," said Krägeloh-Mann going on to add "now we have one patient a month."
The reason why the doctors in Tübingen now see larger numbers of MLD patients is not related to an increase in MLD, but rather to the fact that patients are more frequently referred to specialist centres such as the University Children's Hospital in Tübingen. This has numerous advantages, for patients and doctors alike. "LEUKONET provides MLD patients with access to a Germany-wide expert network where they can obtain information and get a second opinion," said Krägeloh-Mann. However, doctors also benefit from the network in that as they see more MLD patients they gain more knowledge about the course and symptoms of the disease.
LEUKONET has collected data from 70 MLD patients and assessed the motor symptoms of MLD patients using a score developed by Krägeloh-Mann’s colleague Dr. med. Christiane Kehrer. “The acquired data now enable us to make more reliable statements on the progression of the disease than was possible several years ago when it was only possible to analyse MLD cases individually,” said Krägeloh-Mann. It is now known that MLD is characterised by different aetiopathologies, which are caused by different gene mutations. Late-infantile MLD is characterised by the much earlier onset of neurological symptoms than juvenile MLD which usually manifests between the ages of three to ten. The much rarer adult type of MLD initially manifests in uncharacteristic behaviour disorders before neurological symptoms come to the fore.The goal of the project is to build up detailed knowledge about the disease symptoms and make it possible to diagnose the disease earlier than is currently the case. However, it is still a long process before the symptoms are correctly interpreted. “We know children who are under the care of school psychologists or receive medication due to behavioural changes for many years before someone realises that the changes are symptoms of MLD,” said Krägeloh-Mann. However, the point at which a diagnosis is made is critical for the treatment of MLD. It is now known that stem cell transplantation is able to prevent progression of the disease when carried out in children displaying only a few neurological deficits at the time of diagnosis. “In 2001 in cooperation with paediatric oncologists we were able to transplant a child suffering from MLD with stem cells. The disease symptoms in this particular patient have not progressed and the disease has remained stable,” said Krägeloh-Mann. However, stem cell transplantation is associated with some risks and therefore it is necessary to carefully assess potential risks and benefits. “However, once we know how the disease is progressing we are able to better determine the time slot in which the benefit of the therapy clearly outweighs its risks,” said Krägeloh-Mann. Another promising treatment option is being developed and is to be tested in a clinical study assessing the effect of enzyme replacement (Shire, USA). “We are working closely with the investigators as our data enable a much more reliable assessment and scientific evaluation of the efficacy of such innovative therapies.”
Further information:Prof. Dr. med. Ingeborg Krägeloh-Mann Managing DirectorUniversity Hospital TübingenDept. of Padiatric and Adolescent MedicineMedical DirectorDept. Neuropaediatrics, Developmental Neurology, Social Paediatrics Hoppe-Seyler-Str. 1, 72076 Tübingen Tel.: +49 (0)7071-29 84735 Fax: +49 (0)7071-29 5473 E-mail: ingeborg.kraegeloh-mann(at)med.uni-tuebingen.de