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Michael's story

How genetics and immunology diagnosed Michael’s life-long mystery disease.

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Genetics and immunology: a powerful combination in diagnosing and treating rare immune disorders

Patients with rare immune disorders can spend decades seeking a diagnosis that explains their symptoms. This typically involves seeing specialists who span different medical disciplines, only to come away without answers. When all avenues of investigation seem exhausted, doctors often put patients in the ‘too hard basket’, or refer them to mental health services. And in the meantime, patients are not only living with the uncertainty that comes with a lack of diagnosis, they’re living with a range of debilitating symptoms too.

Michael found himself in this exact situation. For forty years, he’d been searching for a diagnosis that would explain his mysterious immune disorder, which left him feeling like a car running on an empty tank.

Michael experienced a range of symptoms, including chronic tiredness, brain fog, poor libido, persistent diarrhoea and sore joints. Over the years, he’d seen GPs, immunologists, a respiratory physician, an oncologist and finally, a psychiatrist. But none of these specialists could explain why he wasn’t well or provide him with effective treatments.

The turning point for Michael came when he developed Kaposi’s sarcoma at age 52. Kaposi’s sarcoma is a rare cancer of the cells of blood and lymphatic vessels. It is usually only seen in patients who are HIV positive. However, Michael was HIV negative.

This unexpected symptom triggered Michael’s referral to CIRCA – a Garvan-initiated multidisciplinary team of researchers and clinicians who investigate the causes of rare immune diseases. Before his referral to Garvan, Michael had lost hope of ever receiving a diagnosis. But Garvan’s research at the intersection of genetics and immunology would change this – and his life.

Michael’s blood sample was sent to Garvan, where postdoctoral researcher Dr Jin Yan Yap examined it in detail. Dr Yan Yap discovered that Michael’s immune system was exhausted, due to abnormal white blood cells. Based on this finding, Michael’s sample was sent for whole genome sequencing, which uncovered a variation in his CTLA4 gene.

CTLA4 helps regulate the immune system by preventing it from becoming overactive or hyperstimulated. Michael’s variation meant that his immune system wasn’t being kept in check, leading it to be chronically activated – even when it didn’t need to be. Hyperactivity of the immune system is followed by an inevitable crash. Since Michael’s immune system never slowed down or rested, it had become exhausted, causing his fatigue, stomach upsets and sore joints. This variation in Michael’s genome also provided a possible explanation as to why he had developed Kaposi’s sarcoma, which occurs when the immune system is compromised. His exhausted system was no longer able to eliminate abnormal cells, leading to cancer.  

“If we apply what we’ve learnt in genetics to diseases of the immune system, we are able to provide diagnoses for patients like Michael, at a genetic and molecular level,” says Dr Pai Dai, who was overseeing Michael’s case at Garvan. “It allows them to get closure.”
Dr Pai Dai

But closure wasn’t the only benefit of Michael’s diagnosis. Dr Dai knew of a readily available drug called Everolimus that could treat Michael by restoring the function of his CTLA4 gene. After commencing treatment, Michael’s immune system starting operating at a normal pace, instead of being hyperactive and exhausting itself. As a result, Michael’s symptoms improved and his cancer went into remission.

Michael’s genetic diagnosis identified an effective treatment that changed his life. But it also helped others. Through CIRCA’s network with collaborating hospitals – including Westmead Hospital, The Children’s Hospital Westmead, St Vincent’s Hospital and Royal Prince Alfred Hospital – its team identified other patients with the same disease as Michael and offered them treatment, leading to improvements in the healthcare and wellbeing of many patients who were also seeking answers.

While genetic sequencing technologies are still in their infancy and we have much to learn about the immune system, stories like Michael’s are proof of how human health can be radically improved by harnessing the power of genomics.

Read more about CIRCA’s groundbreaking research.