Finding the Zebra

All parents desire a healthy child, but as we all know, sometimes our “perfect” children have medical issues that are difficult to understand and even harder to treat. So it was for my son. His birth was wonderful, though quite unremarkable, medically speaking.

It did not take long for me to realize that something was not quite right. The most obvious clue in the early days was my son’s lack of eye contact and feeding problems. He had a lot of difficulty breastfeeding and after about 8 months, I weaned him and tried formula. It made things worse. He vomited all formula, milk based, soy formula. It didn’t matter. The doctors finally tried to address the vomiting and sent us to a gastroenterologist. There the doctor suggested that we try hydrolyzed formula. My son refused it entirely. We finally found a toddler formula that was milk based which he seemed to tolerate.

At a year old, he was below the 3rd percentile on the growth charts. His milestones were coming along slowly. He walked at 18 months. He started talking. I felt like “things will be okay” but things were not. It was just beginning.

He started having white bowel movements. They were white white white. It was so incredibly odd. The doctor tested liver function but it was fine. After a FEW WEEKS the weird diapers stopped for a while. Then he had black and tarry bowel movements. Weeks later he started having pale large, bulky, greasy, smelly bowel movements. This is a something that is often seen in malabsorption syndromes or in cystic fibrosis. His doctors at this point wanted to test him for cystic fibrosis and celiac disease. The sweat test (CF) was negative and the celiac markers were non-existent.

At this point, we have a multiple issues and no answers anywhere. We were just at the beginning of what I now call our diagnostic odyssey.

Our family moved to Singapore when our son was 4 years old. He was still a small kid, prone to vomiting, didn’t eat very well. He started to seem very typical in many ways. He was talking and playing with his sisters and brother. But there was always something a bit off.

At his new school in Singapore, his teachers immediately identified his gross motor skills as being far behind. I wasn’t really aware until it was brought to my attention. He couldn’t jump, his balance was poor, coordination, lacking. I took him to the pediatrician and she sent us to the cardiologist (heart murmur), GI (weight), neurologist (seizures?), endocrinologist (growth), and genetics (answers). It was an extensive work up and there were many flags though nothing diagnostic. Little did I know that medical crises to come.

I wrote out some notes on his medical journey. It has been extensive, and pulled us in many directions. When doctors ask for a medical history, it is not easy to start. Where? What is relevant?

1. Pregnancy and birth
   1. Born at exactly 40 weeks of pregnancy after an artificially induced labor that lasted approximately 5 hours
   2. Birth weight 8lbs, 5 oz
   3. APGARS, perfect

2. Birth-3years
   1. Some feeding problems were observed early on
   2. Breastfeeding was stopped at 8 months due to slow growth and poor feeding. Switching to formula made these issues worse. He would vomit cow’s milk formula. Tried soy based formula, same result. He would not accept hydrolyzed formula. Eventually found an organic formula for toddlers (milk based) that he did ok with.
   3. Milestones were achieved at the later end of normal development. He walked at 18 months.
   4. He was under the care of a GI doctor in NYC. They tested him for celiac disease and cystic fibrosis (sweat test) Both were negative.
   5. He started having white poops as a toddler. This went on for weeks. Later he started having dark grainy poops. Then he went back to having white poops. We went through this cycle a few times. Lots of testing, no diagnosis other than blood in the stool. He also experienced ongoing large, bulky, greasy, and light colored and foul smelling poops. Eventually with potty training, I stopped seeing the poop and didn’t realize there were continuing issues until a number of years later in Singapore

3. Age 4-9 
   1. We moved to Singapore in December 2010 when he was 4 years old.
   2. I enrolled him in a Chinese immersion preschool and they noticed that he had physical delays in both fine motor and gross motor skills. He couldn’t jump with both feet off the floor. He had significant coordination problems. He struggled to write and use scissors (Chinese kids all start writing very young, so I figured they were being too aggressive)
   3. The Chinese school also weighs and measures the kids regularly and he was small by Chinese standards. His weight was always low.
   4. The school called frequently to have me pick him up because he would throw up after eating or he would lay down and during the day and sleep. He didn’t have a fever. He wasn’t sick, but he was not eating and not acting normally.
   5. Once he started throwing up, it would go on for hours. After the first couple of times during a vomiting episode, he would dry heave or vomit bile.
   6. I started taking him to the emergency room during these episodes and they would administer an antiemetic and send us home.
   7. I finally scheduled an appointment with his pediatrician to go over all these things and she sent us to see a cardiologist, neurologist, endocrinologist, and geneticist. Cardiology noticed a heart murmur, but an echocardiogram revealed it to be insignificant. The neurologist did a few exams including an EEG and MRI. Both were normal. The geneticist did a microarray and it showed a 261kb deletion at 17q21.33. The endocrinologist suspected growth hormone insufficiency and blood testing confirmed low IGF1. After multiple tests showing low IGF1 and high growth hormone the doctor suggested we try growth hormone injections. We went through with these injections for 3 weeks. Retesting IGF1 showed a small improvement in growth hormone.
   8. Within days, he started throwing up. I took him to the ER again and he threw up as we entered the triage area. The hospital was very familiar with my son at this point and they took him back right away and did some immediate testing that showed High Anion Gap Metabolic Acidosis and high ketones. The urinary organic acids showed elevated levels of EHA-2 and EMA in addition to dicarboxylic aciduria. The doctors ran tests which suggested a disorder of metabolism involving the electron transport chain. After stabilizing him, we were referred to a doctor at NUH, Denise Goh. GOH Li Meng, Denise – NUS Yong Loo Lin School of Medicine 
   9. Denise Goh met my son and came up with a plan to test him for various inborn errors of metabolism during the next episode. We didn’t wait long, within weeks we were back in the hospital. Further testing didn’t clarify things, unfortunately. He was in and out of the hospital with the same metabolic acidosis. Finally Denise Goh suggested we try a feeding tube to help with his weight and keeping him fed when he is sick. The doctor did an upper GI study and showed regurgitation from the duodenum. Lower GI study was abnormal with very long transit time and showed significant inflammation. At this point Denise wanted to rule out MNGIE (Mitochondrial neurogastrointestinal encephalomyopathy) and so his thymidine phosphorylase was tested. The results were normal.
   10. A PEG tube was placed under general anesthesia and a muscle biopsy was done. Post-operatively, he was taken to ICU due to metabolic acidosis. Within 24 hours, he had stabilized and we were sent back to the floor. He was discharged soon thereafter. He had spent 3 weeks in the hospital getting tested for things. 
4. Age 10 to present, Brazil
   1. We moved to Brazil in April 2015. my son was using a Mic-Key button at this point and we were using a feeding pump to slow feed him at night. He put on a few kilos of weight in face and abdomen. In Brazil, we lost support for the feeding tube. Supplies were difficult, if impossible to come by. We continued using the supplies we had, washing and reusing feeding bags. Eventually we used our last Mic-key button and after that started weaning him from the night feeds.
   2. After arriving in Brazil, we noticed that he began craving salt and eating packets of it whenever he could get his hands on it. 
   3. I found him an endocrinologist and she felt like he had an adrenal disorder, involving insufficient cortisol. We did an ACTH challenge and it showed a marginal response. I didn’t think much and his doctors were reassured.
   4. Two months later… back in the emergency department and my son’s blood glucose is 10 mg/dl and his cortisol is 5 and ACTH undetectable. Diagnosis: Central adrenal failure
   5. This is not everything. He is now 14 years old and below the 1st percentile in height and weight. I’m convinced there is more to his story and hopefully more that can be done to help him.
5. We are now in the US and trying to get some answers. They may never materialize, but as long as he continues to grow and thrive I am happy.

Inborn errors of metabolism are a group of diseases where a genetic defect blocks a metabolic pathway, resulting in a single enzyme dysfunction. When metabolic pathways are blocked the consequences can in some cases lead to disease. The downstream effects of a missing enzyme can affect many parts of the body. These effects lead to the clinical presentation of a disease.

Soon after birth, newborns are tested for these inborn errors of metabolism. It is very helpful to identify some of the very serious and very treatable IEMs before they cause significant damage. Phenylketonuria (PKU) is an excellent example. In this disorder, there is a deficiency or absence of the enzyme phenylalanine hydroxylase (PAH), which processes the amino acid into another amino acid, tyrosine. Amino acids are the building blocks of proteins but when they are not fully converted into their requisite proteins, they accumulate in tissues, like the brain, causing intellectual disability and seizures. The treatments for PKU can prevent this tragedy and the affected person can have a normal lifespan. They must follow a diet that is low in phenylalanine and follow that diet for life. For other IEM, the results are less successful. Tay-Sachs disease is another such disorder where a mutation in the HEXA gene leads to the buildup of GM2 ganglioside within the neurons that leads to loss of motor function and death within a few years.

When my son showed up at the emergency room experiencing metabolic acidosis with high ketones. He was 8 years old. We had experienced ongoing episodes of vomiting and lethargy and weight loss and doctors could never explain it.

The differential diagnosis for metabolic acidosis with high ketones are typically metabolic disorders.

• Fatty Acid Oxidation disorder
• Ketone body utilitzation disorder
• Interference in the mitochondrial respiratory chain
• Organic Acidurias

There are 2 ways the organ systems of the body communicate. Either the communication is electrical (nervous system) or it is chemical (endocrine system). Chemical communication in the body is important for many life functions including managing growth and reproductive cycles, dealing with stress and thermoregulation. Whereas the nervous system communicates in instantaneous, short-lived and direct fashion, the endocrine system sends signals more slowly and more generally over a sustained and sometimes cyclical time frame.

The adrenal glands are part of the hormonal regulatory system in the body. They are small glands that sit on top of each kidney. Each gland consists of a outer cortex and an inner medulla. The cortex produces steroid hormones like corticosteroids (cortisol) and mineralcorticoids (aldosterone) and small amount of male sex steroid hormones. The medulla produces hormones like adrenaline which help regulate aspects of the sympathetic nervous system.

In adrenal insufficiency, there is an abnormal production of these hormones. Primary adrenal insufficiency is a disorder that originates in the adrenal glands where there is an insufficient production of cortisol and sometimes aldosterone. Cortisol production is increased during times of stress. The function of cortisol is mobilize energy stores for use by the body so it increases blood glucose levels. If this hormone is not being produced, blood glucose levels can drop to dangerously low levels.

Enter my son. He was acting a little odd one day. We were out as a family at a park with food trucks and I had gotten my son a cheese pizza. It’s his favorite. Instead or eating, he laid on the ground and refused to get up. He stopped responding. He wanted to sleep. I had seen him decompensate before but this time I didn’t have a glucometer or ketone testing strips. I called an Uber and packed him in the back and went straight to the hospital. We was talking in the car, but quite nonsensically, almost sounding drunk. In the emergency at the hospital, he was taken back right away. Blood glucose testing showed sugar levels 10 mg/dL or 0.55 mmol/L. Normal blood sugar should be between 70-100 mg/dL or 4-7mmol/L. The doctors were surprised he was still conscious. They immediately tested his cortisol and ACTH levels among other things. Both his ACTH were undetectable.

At this juncture, doctors diagnosed him with Secondary Adrenal Insufficiency. What is SAI and how is it different from Primary Adrenal Insufficiency?

In Secondary Adrenal Insufficiency, the pituitary gland located deep in the center of the brain, does not produce sufficient levels of Adrenocorticotropin to stimulate cortisol production in the adrenal glands. There can be a variety of causes including a structural defect in the anterior pituitary or a tumor.

To treat SAI, it is necessary to dose glucocorticoids at regular intervals and increase such dosages during times of stress. Often aldosterone levels can be affected as well which may require supplementation with mineralocorticoids.

My son probably has a partial adrenal insufficiency, but I don’t think that has ever been his real issue. It is secondary to the metabolic disorder that we have yet to diagnose.

My family has just tested with 23andme and we learned that my son and I are carriers for a congenital disorder of glycosylation, type 1a. We have the R141H variant, which appears to be the most common. It seems though that this particular variant is disease causing on its own as there it has never been documented in the homozygous state.

You can read more here.

We have just received the results of my son’s muscle enzyme analysis. The report says its completely normal. Instead of low enzyme levels, a common finding in mitochondrial disease, his levels are high in 3 different complexes.

We have reached the end of diagnostic options. His doctor says our last option is Whole Exome Sequencing (WES).

So far we have a mild muscle involvement, dysmotility, and ketoacidosis with hypoglycaemia. He fits no profile for metabolic disorders and was negative for the mitochondrial disorders (the 22 most common). His muscle biopsy was basically normal though did not rule out mitochondrial disease.

Right now I’m considering our options. He is doing really well with the G-tube and has put on around 5 kg in 2 months after not gaining for 2 years. So on the one hand, things are going well. I’m disinclined to pursue any invasive or painful tests for now. Intestinal biopsy is on the table due to the intestinal issues, but since things are going well, no one  (including me) is very interested in pursuing this option.

Basically, we are left with WES and getting a second opinion. I’m inclined to do the latter as I really need some new eyes to look at his issues.

Mitochondrial Neurogastrointestinal Encephalopathy.

Our son is currently being evaluated for this condition.  It is an autosomal recessive condition, in which each parent contributes one defective TYMP gene, which encodes for Thymidine Phosphorylase. The disease often presents with gastrointestinal motility and eye problems. It often leads to cachexia, peripheral neuropathy, and leukoencephalopathy.

Thymidine Phosphorylase is an enzyme required for DNA maintenance and deficiency results in mitochondrial deletions and abnormalities.

The current recommended treatment for this condition is a bone marrow transplant, which is able to replace the missing enzyme to therapeutic levels in the body. It’s not likely to improve things, though it may stop the course of the disease.

Read more here:

http://link.springer.com/article/10.1007%2Fs10545-010-9049-y

Update: His MNGIE test is negative. However, his doctor keeps noting it as his clinical presentation is quite similar.

I am going to use this blog to write about current research in medicine and other topics I find interesting. I’m not a doctor or a researcher, but I have an amateur interest in medicine and desire to learn more.