Professor Arndt Rolfs, M.D, discusses the importance of biomarkers in early diagnosis and monitoring
An interview with Professor Arndt Rolfs, a Professor for Neurology and Psychiatry at the University of Rostock, Germany, head of the Albrecht-Kossel-Institute at the University of Rostock and since June 2014 Chief Executive Officer of Centogene AG. Ahead of SSIEM 2016, we had the pleasure of interviewing Arndt Rolfs, M.D, Professor for Neurology, about his opinions on key topics related to the diagnosis of lysosomal storage diseases (LSDs). See below for the discussion and visit the Rare 2 Aware blog agai n for more information from leaders in the rare disease space. Q) What challenges are faced in the diagnosis of LSDs? A) In the case of Fabry disease, many patients experience a 10-12-year delay between symptom onset and diagnosis. This results from either
- misinterpretation of mild/moderate initial symptoms, or
- misinterpretation of the full picture of symptoms as another cause.
Not every patient displays the full combination of symptoms, and the disease can have late onset, which complicates the process. Q) How can we facilitate early diagnosis of LSDs? A) Biomarkers have an important role in early diagnosis and in monitoring to quantify disease severity. [Biomarkers are naturally occurring molecules, genes, or characteristics by which a particular pathological or physiological process, disease, etc. can be identified] We need to make the life of the doctor easier with a simple screening test that can test for several diseases in parallel at low cost. However, once a patient has been diagnosed, the quantification parameters to show the severity of the disease, and whether treatment should be begun immediately or if watchful monitoring continued, is still missing. If this decision is left up to clinical judgement, there is always subjectivity – different specialists may place different levels of importance on different symptoms. Therefore, an objective parameter, such as a biomarker, would again make the life of the doctor easier. Q) What is the situation of biomarkers currently used in the diagnosis of LSDs? A) All current biomarkers have limitations – for example, they may not actually be involved in the pathophysiology of the disease, or they may not be easily measured, especially when taking into account the logistics of storing and transporting biological samples. Therefore, current biomarkers still require validation. Q) Are there any new biomarkers on the horizon for use in the diagnosis of LSDs? A) Many laboratories are investigating new or improved biomarkers for Fabry disease and I am confident that within 24 months, there will be new sensitive and specific biomarker seen in literature. Currently, the best biomarker we have available is globotriaosylsphingosine (lyso-Gb(3)), but it is far from ideal. My lab is working on improving lyso-Gb(3) by using high-sensitivity mass spec analysis to identify variants of this molecule within the mixture that may be a better biomarker. We are also investigating two other targets as possible new biomarkers. We are also researching a biomarker for Hunter syndrome based on a metabolite involved in the pathophysiology of Hunter syndrome for use in dry blood spot (DBS) testing. Q) What are the methods of testing for LSDs? A) Dry blood spot testing is probably the best method we can offer patients at present. It is minimally invasive – blood-taking is a routine procedure worldwide – and dry blood spots are stable in different climates/conditions. Q) What is your view on the importance of newborn screening for LSDs? A) As a parent, I would be interested to know, but as a physician I have to balance two things:
- the burden/consequences placed on the family/patient when a positive result is found
- the ability to offer a solution, i.e. treatment, soon.
The situation is different for different diseases. In Pompe disease, the argument for newborn screening is more straightforward than for Fabry disease. Pompe disease should be part of the newborn screening programme because there is a severe neo-natal form for which each week of delay will decide the overall prognosis and life expectation of the patient and therefore earlier diagnosis and treatment has a very significant effect. In Fabry disease, there is much more heterogeneity and female patients can be asymptomatic (related to disease being x-linked and effect of x-inactivation). Additionally, it is often the case that treatment is not needed for the first decades of life, therefore there are argument against newborn screening. Q) Can we predict the disease phenotype from the patient’s genotype? A) Currently, the genotype-phenotype correlation is not straightforward in Fabry disease and it is difficult to predict disease severity from DNA. I believe that within 5 years or so, once we have a good biomarker, we will need a systematic prospective study to analyse genotype, biomarker, and lyonisation status and we will be able to establish a correlation between nearly all genotypes and phenotypes. Q) What is your opinion on the importance of pedigree analysis? A) Pedigree analysis is super important and should be carried out in all of the hereditary disorders. Pedigree analysis must go hand in hand with genetic counselling because, otherwise, it is unfair on the patient. I carry out pedigree analysis as standard practice. It is offered to all index patients and I look at 3 generations. Then, with the permission of the patient, we can directly contact family members. Q) What are the key challenges in disease management of LSDs? A) The most important thing is to improve the life of the patient. Home treatment can be a good solution. However, it doesn’t suit everyone as some patients like the regular interaction with hospital physicians. Biomarkers for monitoring disease progression will be a valuable addition to this decentralised approach because ideally a patient could have blood taken every other week for biomarker or antibody testing, alongside their usual treatment regimen, so that disease monitoring can also be decentralised. With this system the patient would only need to see their physician every 6 months or whenever disease progression is noted. Q) Could country-wide/Europe-wide centralised reference centres be useful? A) You need a minimum number of patients that require a particular test to support the existence of a lab in a particular area, such that the lab has routine familiarity with the test and appropriate quality control measures. This needs to be balanced against the need for local language communication and a short line of communication. Therefore,1 or 2 laboratories per country is good. Disclaimer: The views expressed in this post do not necessarily reflect the views of Shire INTSP/C-ANPROM/RDBU/16/0032 September 2016 The post Professor Arndt Rolfs, M.D, discusses the importance of biomarkers in early diagnosis and monitoring appeared first on Rare2Aware.