A Long Journey of Mysterious Disease Gets Right Back on Track

One day in summer, it was a simple routine day doing my clinical demonstration for my medical students. A 4th year female student introduced me to Emily, a 44-year-old woman who looked depressed and felt sick of failed medical treatments. The student was curious about Emily’s condition as it related to genetics. I then talked to Emily and her mother and asked for their consent for a demonstration involving her case. In this hospital admission, Emily was admitted for intravenous immunoglobulin (IVIG) infusion to treat the neurological condition called chronic immune sensory polyradiculopathy (CISP). However, this was her eighth round of treatment, and Emily felt that her symptoms had never improved. She still had sensory disturbances and difficulty walking.

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I continued to hear Emily’s story from the student. Emily had regular follow-ups with multiple medical specialists for more than five years. She began seeing the ophthalmologist due to a reduced vision problem, leading to maculopathy of both eyes being subsequently diagnosed. In the meantime, she was also referred to see a rheumatologist, since she also had pain in both legs. She was diagnosed with an autoimmune disorder, called Behcet’s disease, and she was then treated with intravenous high-dose steroids and immunosuppressive drugs. A few months after initiating immune treatment, she developed emotional fluctuations and depression. The psychiatrist and neurologist agreed that the adverse reactions were due to both the steroids and the negative response to the illness.

Emily’s symptoms had been stable. The mother used to say, “not worse, not better”, but she had to cope with the steroid side effects such as the moon-like face, obesity, the elevation of blood glucose, skin cracking, and the increased risk for unusual infections. Immunosuppressive drugs also caused her to become immunocompromised. Then, new symptoms developed, Emily started to have progressive difficulty walking over the past two years. Her nerve conduction study displayed abnormal findings in both her legs, consistent with either sensory neuropathy or ganglionopathy. She was examined extensively, including blood tests, brain and spinal cord MRI, and a lumbar puncture (collecting the cerebrospinal fluid by penetrating a needle into her back). The medical team decided to treat CISP by introducing costly IVIG infusions.

Both Emily and her mother wanted to withdraw from all treatments. They were desperate and pessimistic about having a normal life. I asked for all the medical histories again with my clinical genetics perspective since I needed to know the information in their own words. Surprisingly, the mother informed me that Emily had clumsiness since childhood. In addition, Emily had never walked like ordinary people, and she seemed to have frequent leg shaking, especially climbing the stairs. Next, I demonstrated a clinical examination with the students and found that Emily had poor muscle coordination and balance (ataxia), numbness of both legs, and loss of joint and vibration senses.

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After gathering all the necessary clinical information, I discussed with the medical students that various genetic causes would be suspected. Immediately, I called the neurologist and rheumatologist for a comprehensive discussion and raised the hypothesis that Emily’s condition might be genetic. The day after, our multidisciplinary team decided to undergo a genetic investigation. I recommended Emily for whole-exome sequencing by decoding more than 20,000 genes in our cells to save time and cost. Afterward, I contacted 3billion’s laboratory in Korea since we had a collaborative project, and Emily’s blood sample was then processed.

When the results came back on my online portal, I was glad to solve Emily’s mystery. Relying on all clinical information and genetic findings, Emily had a genetic condition called Ataxia with Vitamin E Deficiency (AVED). Next, we confirmed the deficient vitamin E level in Emily’s blood that was consistent with the genetic diagnosis. Therefore, we proved that she did not have immune dysregulations like Behcet’s disease or CISP. It meant that she did not need to take the risk of taking steroids and immunosuppressive drugs anymore. Furthermore, we discovered a new treatment for Emily using vitamin E replacement therapy.

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AVED(MIM# 277460) is the genetic condition caused by the mutation (gene mistake or faulty gene) in the TTPA gene that regulates vitamin E metabolism. Following the TTPA mutations, the patient commences severe vitamin E deficiency that manifests in many organs, including ataxia, gait impairment, profound sensory disturbances, eye impairment(maculopathy and retinitis pigmentosa), and a few cases report abnormal heart condition (cardiomyopathy). High-dose oral vitamin E supplementation would help prevent further neurological deterioration. That said, treatment early in the disease process may help reverse ataxia and neurological symptoms.

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One year later, Emily and her mother came back to my genetics clinic with bright smiles. They were happy to receive the proper treatment for her actual genetic disorder. Eventually, Emily did not need to take the risk of taking steroids, and immunosuppressive drugs. Vitamin E supplementation alone was expected to stabilize her clinical conditions. Lastly, I read a reflection note from a medical student who presented Emily’s case on that day, “My heart was like a blossom when Emily got right back on track, genetic technology allows us to solve the patient’s puzzles and explore new treatment opportunities.”

Dr. Objoon Trachoo's biography

  1. Objoon-Trachoo
  2. Dr. Objoon Trachoo has an Associate Professorship of Medicine at the Faculty of Medicine Ramathibodi Hospital, Mahidol University in Bangkok where he works as a consultant clinical geneticist and principal clinical molecular geneticist. His special interests include neurodevelopmental disorder, inherited cardiovascular conditions, and preimplantation genetic testing for monogenic disorders. He is currently running several research projects using next-generation sequencing to search for the etiology of epilepsy, cardiomyopathy, and other rare disorders.

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