The "not so rare" reality - a 28 year long diagnostic odyssey

Arushi Batra

Neha (Vinay’s sister; name changed on purpose) walks into Vinay’s room in the long term care, which has been his new home since 2014. He has no strength to even sit, uses a wheelchair, cannot eat solid meals, and cannot speak properly due to shallow breathing, but his face and eyes light up with smiles and happiness as soon as he sees his sister. He tickles her stomach and gestures that she has become fat. Sibling love is the purest kind of affection. However, there is a long and complicated struggle behind these smiles and love that only some people understand.

Vinay (name changed on purpose) and his family were exhausted, frustrated, and yet without a diagnosis in 2014, for 28 years , after dozens of expert visits , dozens of genetic testing, and MRIs. Vinay was born on June 24th, 1983 , and by the time he was three years old, he was suffering from chronic diarrhea. He was behind in several developmental milestones, such as walking or talking, and by the time he was three years old, he couldn't even suck at a bottle. He was placed in a special education program within a mainstream public school since he was extremely slow and it was becoming challenging for him. Vinay had already been to a handful of specialists, but none of them could figure out what was wrong with him. His sister was just eight years old at the time of his birth, and despite knowing he was different, she couldn't understand what was wrong with her brother. Vinay was tormented a lot at school, and by the time he was in Grade 3, he had also started rebelling. Though he never had any behavior problems at school and was never aggressive with his peers. He also never caused any fights and was respectful with teachers. He was more shy and withdrawn. And had trouble sitting still and focusing . Because he was unfocused and fidgety, he was taken to a psychiatrist and diagnosed with ADD (Attention Deficit Disorder). Vinay was put on a prescription (drug: Ritalin) that he didn't like and would spit it out as soon as someone looked away. It was difficult for the parents to keep up with his care because he required constant attention, so they worked rotating shifts to accommodate him. He did, however, complete his community college vocational training program and graduated. He worked until he was about 29 or 30 years old. Throughout these years, he saw a variety of doctors and had a battery of tests to screen for Parkinson's disease, Multiple Sclerosis, Cystic Fibrosis, and a variety of other conditions. However, none of them were conclusive enough to provide him and his family a diagnosis, leaving him and his family in despair. His diarrhea had almost subsided by this point, but his food patterns had become irregular. He was underweight, and he didn't seem to be thirsty or hungry at all. His parents were becoming increasingly concerned, and a few more visits to geneticists and specialists resulted in a few tests for Leukodystrophies, but none could explain what was wrong with him. Vinay was around 20 years old when he became affected by all of these unsatisfactory visits and ultimately requested his parents to stop. He thinks that none of them can figure out what's wrong with him and that he just wants to be alone. He was very frustrated.

Since he lacked proper comprehension skills and other cognitive abilities, he got a complete IQ workup done. IQ (Intelligence Quotient) is a total score obtained from a set of standardized tests meant to evaluate human intellect . When the results came in 2012 , he was told that he has an IQ level equivalent to a grade 7 kid and mathematical abilities equivalent to a grade 3 kid, clearly indicating delays and deterioration in cognition and motor skills. He was also losing his ability to stand and started collapsing on a frequent basis.

Vinay and his family were so disturbed by everything that they decided to travel to India as a last resort to try to acquire a diagnosis. They went to an Indian neurologist in Trivandrum, who after evaluating him clinically and reviewing his medical history came up with five clinical possibilities, the most likely of which being Cereberotendinous xanthamatosis. To confirm his diagnosis, he wanted to conduct a few tests on his urine and blood sample. They returned to Canada with the Indian doctor's detailed clinical notes. Because these next-generation based tests were not easily available in 2012, even in Canada, they had to be shipped to the United States. The terrible thing was that, because these were examined and requested by an Indian doctor, most Canadian doctors declined to look deeper. One elderly doctor, though, persevered, and the samples were sent to the United States, where they were ultimately confirmed in 2014. Cerebrotendinous xanthomatosis was the diagnosis (CTX)

The Human genome on the whole is quite large, with more than 3 billion alphabets including 4 nucleotides A, T, G, C located on something like a chain and organised into packages known as chromosomes. Each chromosome contains many genes. By definition genes are the functional unit of inheritance. Some of these genes act as “instructions” for a cell to make a protein. Now for any inherited disease to occur, its centre is attributed to variations in the DNA. A mutation occurs when the sequence of DNA changes. Mutations can occur as a consequence of DNA copying errors during cell division, exposure to ionising radiation, exposure to substances known as mutagens, or viral infection.

Cerebrotendinous xanthomatosis (CTX) is one such rare autosomal recessive genetic condition caused by a mutation in the CYP27A1 gene. The CYP27A1 gene instructs the production of an enzyme known as sterol 27-hydroxylase. This enzyme is found in the energy-producing centres of cells (mitochondria), where it participates in the process of breaking down cholesterol into acids that may be utilised to break down fats (bile acids). Sterol 27-hydroxylase, in particular, breaks down cholesterol to produce chenodeoxycholic acid, a bile acid. The major route for cholesterol elimination in the body is the synthesis of bile acids from cholesterol. The enzyme sterol 27-hydroxylase is important for maintaining healthy cholesterol levels in the body. When the disease CTX occurs as a result of a mutation in this gene, it results in a lack of this enzyme, which prevents cholesterol from being metabolised. Cholesterol and a related substance called cholestanol accumulate in nerve cells and membranes as a result, putting the brain, spinal cord, tendons, eye lens, and arteries at risk of injury. As a result, Cholesterol and a similar substance called cholestanol build up in nerve cells and membranes, posing a risk of injury to the brain, spinal cord, tendons, eye lens, and arteries. Children with the condition may suffer diarrhoea and cataracts, while adolescents with the condition may develop benign fatty tumours (xanthomas) of the tendons. CTX, if left untreated, can cause progressive neurologic disorders such as seizures, cognitive impairment, and coordination and balance issues (ataxia). Coronary heart disease is a very prevalent condition in such patients. During infancy, some people who develop late-onset CTX symptoms had cholestatic jaundice. Even for twins with the identical defect in the CYP27A1 gene, the specific symptoms and course of this condition can differ significantly. Long-term chenodeoxycholic acid therapy has been shown to be beneficial in treating affected people.

Vinay's treatment plan was put in place as soon as he received his diagnosis. The medicine was not manufactured in Canada at the time and had to be imported from Germany. His family thought that he should be sent to a long-term care facility since he had substantial deficits in most motor skills and had lost his ability to balance at that time. They are regarded as essential individuals since they are his parents and caregivers, and as a result, they were allowed to meet him despite the Covid situation. However, there have been hurdles, as they have had to conduct frequent PCR and rapid antigen testing before seeing Vinay since they pose a huge risk to him.It has had an emotional impact on him, but he is handling it well. Because long-term care institutions were given priority in Canada, Vinay was able to get three doses of the vaccination, which is a big comfort. He is, however, still confined to his wheelchair, and even getting him into this involves picking him up and then positioning him in it. His parents continue to see him on a daily basis, and his mother continues to cook for him , preparing a puree to feed him. They acknowledge that it has been a difficult road and that they wish they could have gotten the diagnosis sooner. They wish they may have had a better life if the clinicians had been curious enough to explore for symptoms and had maintained a lateral thinking instead of only looking for what was prevalent. Regardless, because of the medication, the doctors have advised Vinay to undergo frequent eye tests for cataracts, which are prevalent in CTX patients, as well as a comprehensive cardiac workup once a year.

Vinay is special in his own way, despite the fact that he has a disability. His parents say that he has an exceptional sense of spelling and hence communicates effectively with a spelling board. His xanthomas have not grown in size as a result of the treatments, indicating that the therapy is effective. He also has a lot of affection for his sister's children and is emotionally attached to his family. They have accepted his situation and hope for nothing more than policy reforms for other children and patients in order to enable them to be aware of the condition and begin treatment as soon as possible.

Although CTX is an uncommon disorder, it is likely to be underdiagnosed since the presenting signs and symptoms are often nonspecific and overlap with other, more common conditions. Patients vary in terms of signs and symptoms, severity, and age of onset. The condition progresses and can be disabling or fatal, especially in cases of neurologic manifestations such as intellectual disability, autism, behavioral and mental issues, and dementia, to name a few. As a result, they believe that early detection is critical.

Childhood with a disability hasn't been simple, "Why him or why us?" they still ask themselves sometimes. But then they notice how far they've come. There are some conditions that can be treated and managed. To minimize damage, we only need to diagnose them early.

About the author

Ms Arushi Batra is a graduate student at the CSIR Institute of Genomics & Integrative Biology (CSIR-IGIB) and her research focuses on the genomics of Intellectual Disability as part of the GUaRDIAN initiative. All opinions expressed in this article are based on a real life interview story with a patient and his family that was conducted by the author.

She can be reached at @Arushi_Batra28 on Twitter