We’re pleased to feature this interview with Dr Brad Lewis, Medical Director of Machaon Diagnostics. A hematologist with background in biochemistry and focus on thrombosis and hemostasis, Dr Lewis lectures both in the US and internationally on the clinical and laboratory approaches to diagnosing atypical Hemolytic Uremic Syndrome (aHUS) and Paroxysmal Nocturnal Hemoglobinuria (PNH).
With expertise in the use of genetic sequencing data, Dr Lewis has provided clinical consultation on thousands of suspected cases of aHUS sent to Machaon Diagnostics for complement and coagulation gene sequencing. The aHUS Alliance Global Action team appreciated this opportunity to ask Dr Lewis a few questions about genetic testing and its importance for aHUS patients and their care.
There are four topics which framed our interview with Dr Brad Lewis, Medical Director of Machaon Diagnostics:
1. Is aHUS genetic testing only useful for diagnosis confirmation or prognosis? How can information learned from aHUS genetic screening indicate details of high interest to patients and their families such as: managing disease treatment and progression, transplant, pregnancy and family genetics, or withdrawal from treatment and relapse risk rates?
2. Once an aHUS genetic mutation is identified with testing, will every patient with the same genetic profile experience similar symptoms, duration of illness, and organs affected? Do patients with mutations in the same complement component (such as Factor H, CFH) have the same clinical course and outcome?
3. Feedback or interpretation of genetic test results seem designed for clinical experts rather than patients. Why not a ‘patient friendly’ report of genetic screening results designed to address not just technical aspects but also include ‘interpretation’ or genetic counseling aspects that are centered on patient issues?
4. Many aHUS patients’ are concerned that close family members could be genetically susceptible. Some people are genetically predisposed to aHUS, but remain without onset of the illness. How predictable are results from that aspect, and what are the advantages or disadvantages regarding genetic screening for those with a family history of aHUS?
Thank you to Dr Brad Lewis and the Machaon Diagnostic team for providing their answers to these questions. We welcome the opportunity to interview medical professionals or academics, research groups, clinical trial leads,or others who have interest in any/all aspects of the aHUS space.
Important Notes: Our mission as a global patient advocacy group is to provide information and insight regarding topics which focus on the rare disease atypical HUS, and to provide a collaboration portal through efforts such as the atypical HUS Community Advisory board (aHUS CAB). Medical decisions for aHUS diagnosis and treatment require personalized care based on individual case histories. The aHUS Alliance Global Action group interests are non-commerical, and while our website offers an international network of aHUS expert support for medical professionals our group neither endorses nor provides medical treatment or advice.
I’m a tremendous fan of genetic testing in patients with known or suspected aHUS. In fact, Machaon began offering rapid genetic testing, in part, because I needed it to assist my evaluating patients. That said, I often find myself reminding providers and patients alike that aHUS is a clinical diagnosis, or what is sometimes called a “syndrome”. That means that the diagnosis is strongly suspected when certain findings on the history, the physical exam and in the laboratory evaluation all suggest the diagnosis.
There is no single diagnostic test for aHUS—many blood tests are done and together they can be very suspicious, but ultimately this is a diagnosis of “exclusion”. A patient will present with an uncommon disorder called a thrombotic microangiopathy (what I’ll call TMA for short). This is seen in many disorders—infections, malignancies, pregnancy, heart problems, liver problems, diseases where someone’s own immune system mistakenly attacks them, and others. As the providers work through all the more common possible causes of this TMA, they may not find an answer. At that point they move to rare causes—like thrombotic thrombocytopenic purpura (TTP). That disorder is easily shown to NOT be the cause with a blood test for the ADAMTS13 protein. (If more than 10% of the usual levels of ADAMTS13 are present, then it is not TTP.) At that point, we have “excluded” all the other possible causes of TMA and only aHUS is left—a diagnosis of exclusion.
This is the point where genetic testing usually comes in. At least half of the patients clearly diagnosed with aHUS will have a normal genetic panel. Obviously, we don’t yet understand all the genetic causes of this hereditary disorder. So, having a normal genetic result would not change the diagnosis of aHUS. On the other hand, some people have genetic mutations seen in aHUS but do not themselves show disease. We’ll talk more about this phenomenon later. Diagnosing aHUS is based on the combination of the history, the exam and many labs—ultimately ruling-out other possibilities. In that setting, a positive test confirms the diagnosis, but a negative test would not un-confirm it.
Why then would we ever want genetic testing? The clearest use for the testing is to predict someone’s ability to come off therapy after initial successful treatment. Some genetic mutations (notably complement factor H or CFH) have a very high risk of recurrence. On the other hand, in the absence of any mutation, the chance of recurrence after stopping successful therapy is quite low. This is also true after kidney transplants and almost all kidney transplant patients will have genetic testing. Genetic testing is also useful to screen family members who might donate kidneys—it helps us understand the potential donor’s risk of developing aHUS and in some cases, may predict the risk of recurrence in the recipient, after the transplant. Similarly, pregnancy is a time of high risk of aHUS recurrence. (Podcast link) I never tell patients that they cannot become pregnant again due to the aHUS diagnosis. But, to some extent, the risk of recurrence can be predicted based on the genetic mutation and would alter our therapy during the pregnancy. Lastly, providers are occasionally truly confused as to the diagnosis. I’ve been in that situation myself. In that setting, genetic testing may make the diagnosis and allow rapid initiation of therapy which might have been delayed for further “exclusion” of other diagnoses. This is the reason that Machaon provides rapid testing. When we first began offering genetic testing, the standard wait for results was about 120 days. Even today it is often a month or so. Machaon provides test results in 2 days when there is a sense of urgency and in 5 days when the provider is not in a tremendous hurry. This has been game changing—where previous genetic testing was interesting, it was of no value in the diagnosis of this often rapidly progressive disease. Now, genetic results can be back almost as soon as many of the other more routine test results which are needed. I always remind providers though, that if they believe a patient likely has aHUS, then a negative test does not mean that the patient doesn’t have aHUS.
I mentioned above that aHUS mutations have variable “penetrance”. This means that two patients, even in the same family with the same mutations may have different severity of disease, different organs affected (kidneys, heart, lungs, bowel can all be affected to different extents) and a different course of the disease. In fact, one patient may be severely ill and the other, in the same family have no signs of aHUS ever. This is the case for other diseases as well (A McNeill, 2022, Eur J Hum Genet), where the genotype (the mutation profile) does not predict the exact phenotype (how the disease manifests). (Podcast link) Mutations in certain genes are more likely to result in recurrence in patients who have had aHUS but still will not necessarily result in disease in family members with the same mutation. We don’t yet really understand why this is. It appears that an attack of aHUS is often a two-part attack. A patient must have some genetic predisposition to the disease (although we don’t always know what that gene is) and then some “trigger” to start the attack. One of my elderly patients had been well her entire life until a severe, life-threatening bacterial infection in her blood triggered her first aHUS episode. She might well have made it through her entire life without aHUS. Even in younger individuals with more severe genetic mutations, there is usually some infection, illness or a pregnancy which triggers the attack. The occurrence of this trigger and its severity may help determine whether that individual ever has an attack of aHUS—even though they have an aHUS mutation. Finally, it seems likely that there are “helper genes” which don’t themselves cause aHUS but increase or decrease the chance of aHUS developing in patients who have known mutations.
Remember that everyone is different—we have brown hair or blond, tall or short. We all have uncountable genetic variations compared to others. It can be difficult to decide which variations result in insignificant differences such as “blond versus brunette” and which are “disease causing”. We use several tools to decide whether a given mutation is disease causing or not. But still, we occasionally find mutations which have never been seen before, so that it is impossible to be sure what they mean.
Before Machaon Diagnostics began providing next generation genetic sequencing for aHUS, test results were often either too complex for most providers to understand or so simple that sophisticated providers did not get all the information they wanted and needed. I still get frequent calls from providers who are overwhelmed by the data we provide and don’t understand how to interpret it, and, on the other hand, from others who want us to provide more detail. Consultation is needed for providers, for example, in how to interpret an equivocal result. (Podcast link) Overall, however, the feedback is highly supportive from providers who feel we have found the sweet spot and can back up the report with physician consultation in difficult cases.
Often our reports are provided to the patients themselves. We include my personal cell phone on the report. When patients call, I help them interpret the genetic data. I always remind them though, that aHUS is a clinical diagnosis—to really understand the diagnosis and the role of genetics in that diagnosis requires that someone have all the medical data available to them. I will then often discuss the case with a patient’s provider before discussing the genetics report, in an effort to obtain all the necessary information. Because of (1) the complexity of the diagnosis, (2) the variability of the genetic impact in any individual and (3) the possibility of other, yet unknown, genes playing a role, it is impossible to provide a “simple” report. We do, however, provide a one-line summary at the top of the report: positive, negative or uncertain/equivocal. We discuss what is known about each mutation that is suspicious or known to be pathogenic.
This complexity is quite different from the situation with genetic testing in more clear-cut disorders. I also treated patients with sickle cell disease and hemophilia, and we do genetic testing for Alport syndrome. In these cases, the genetic testing results tell us much of what we should expect for a given patient and may directly help determine treatment options. This is not yet the case for aHUS, although we hope that it may become true as we learn more about the disease.
By the way, the expense of a test can be a barrier to getting patients the right treatment. To remove this barrier, Machaon Diagnostics has partnered with pharmaceutical companies, charities, and other organizations to facilitate no-cost testing for eligible patients.
At this point in time, I am a bit conflicted about genetic testing of family members. On the one hand, knowing that someone is well but has a mutation predisposing them to aHUS would be useful in some situations—it should shorten the time to making a diagnosis of aHUS if they become ill. This can be particularly useful if the physician is unfamiliar with aHUS or reluctant to make the diagnosis. On the other hand, even if a family members’ genetics are negative, there is some possibility that they have a mutation in one of the genes we have not yet identified. If someone has a family member with aHUS—whether or not they have had genetic testing done—they should assume that they might be at increased risk of aHUS, and their providers should move quickly to that diagnosis in the right setting.
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PODCASTS by Dr Lewis about aHUS Topics within this interview
Dr Brad Lewis: aHUS and Pregnancy
aHUS/TMA in Pregnancy, with Richard Burwick, MD, MPH – Assistant Professor, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Cedars-Sinai Medical Center
Blood, Sweat and Smears – A Machaon Diagnostics Podcast (2020)
Dr Brad Lewis: Genetic Testing – what to make of an equivocal aHUS Result
Blood, Sweat and Smears – A Machaon Diagnostics Podcast (2018)