Cleo, Age 1

Our daughter, Cleo, was diagnosed with Pyridoxine Dependent Epilepsy (PDE-ALDH7A1 / antiquitin deficiency) at a little over a year old. PDE is a rare neurometabolic disorder that has recently been recognized by the OAA as an organic aciduria. Antiquitin deficiency results in an inability to catabolize the amino acid lysine, causing a build-up of neurotoxins (a-AASA, P6C and pipecolic acid) in the blood, urine and CSF. While the seizures characteristic of the disorder are normally managed by high dose pyridoxine, the effects of the neurotoxins are more challenging to mitigate. In addition to pyridoxine, a restricted-lysine diet with specialized formula and arginine supplementation comprise “triple therapy”. Even with treatment, however, 80% of individuals suffer developmental delay and intellectual disability.

Perhaps one of the most challenging aspects of this condition is the path to diagnosis. In its classic form, babies are born in a state of epileptic encephalopathy (in some cases the seizures are detected in utero as rhythmic movements felt by the mother or observed via ultrasound). A trial of pyridoxine is typically administered while the infant is in the NICU as part of the neonatal seizure protocol. A third of those affected, however, present with atypical PDE where seizure onset is later. In these cases, it takes a perceptive team to even consider trialing pyridoxine therapy and run the necessary tests to make the correct diagnosis. Unfortunately, at this point in time, the diagnostic biomarker for antiquitin deficiency is too unstable to be obtained from the newborn screen (each time Cleo has her blood tested for her levels, they have to send a frozen sample out of state to a specialized lab and it takes 2-3 weeks to get the results back). Cleo recently participated in a study that looked at the newborn blood spot cards to see whether a novel and more stable biomarker could be used to retrospectively diagnose PDE. The findings are extremely encouraging as all patients with PDE were correctly identified via blood spot card re-analysis. The novel biomarker is therefore viable for the newborn screen and we hope PDE will be added to the list of screened conditions in the not too distant future. It may also mean that her team will soon be able to track her levels more easily and rapidly.

In Cleo’s case, while we enjoyed a smooth, full-term pregnancy and delivery, she was unusually subdued as a newborn. She had an ashen complexion despite repeated normal bilirubin levels, she never cried, and would only feed briefly before falling back asleep. Cleo is my third child. My first two were premature (twins). They were far more alert than Cleo, despite her being almost twice their size at birth. I just sensed something was very wrong. The nurses reassured me that infants are often sluggish at first and to make the most of the peace and quiet as it will be short lived. The lethargy persisted, however, and she never woke up crying for a feed, so I would set an alarm every 3 hours at night to ensure she was fed often enough.

Before we were discharged from the hospital, a pediatrician detected a heart murmur and referred Cleo to a cardiologist. Further testing found an ASD and VSD (a hole between each of the upper and lower chambers of her heart). Initially, everyone naturally blamed Cleo’s reluctance to feed on that. The only person who felt otherwise was Cleo’s cardiologist who was adamant this was not yet cardiac related. In a sense the heart issues served as a red herring. At 2 weeks old, Cleo began to vomit frequently after feeding. She was born at the 75th percentile for weight but by 10 weeks had dropped to 1st percentile. At this point, Cleo was admitted to hospital for failure to thrive and an NG tube was placed. She was also showing some signs of early heart failure so was started on a diuretic. While the diuretic seemed to help, the vomiting continued and the various specialists who saw her found no other issues to explain her failure to thrive. After a week in hospital, the team decided to proceed with open heart surgery to patch the holes. We all hoped her feeding would pick up thereafter but at the back of my mind I was skeptical. While her ashen appearance transformed into a pink healthy glow as she recovered in the PICU, her appetite remained poor and the vomiting continued. I was instructed to fortify my breastmilk with formula to boost her caloric intake but that only made matters worse. It was as if she could not tolerate her food but all tests were fruitless. She was perfectly happy until we switched the feeding machine on, to which she’d become visibly uncomfortable. 

At 5 months old, we reluctantly agreed for the NG to be replaced with a g-tube after she repeatedly regurgitated the tube while vomiting. We accepted that this was just part of her and our lives for the time being. In the meantime, we involved Growing Independent Eaters, a private tube-weaning consultancy, with the hope of weaning her from tube feeding. By 9 months old, her feeding did actually start to improve after we reverted back to expressed milk only and reduced her tube feed volume. I finally felt optimistic; maybe time was all she needed? She also finally started taking some solids. While she was somewhat delayed, she was now able to sit up by herself and was making good progress toward rolling and crawling. Then, at 9.5 months she became ill with a cold. While her cold symptoms abated, during the course of two weeks, she became increasingly fussy and the only thing that comforted her was to be held day and night. This was in contrast to a very happy child who barely ever cried. The fussiness reached what felt like a crescendo when she suddenly fell unresponsive and then started to seize. Altogether the episode lasted about 10 minutes by which point the EMS team was there. Imaging and an initial EEG found nothing amiss. We were told it was just a febrile seizure but, as it so happened, I had recorded a normal temperature just minutes prior. We saw a neurologist and I immediately mentioned her fussiness (which continued post-seizure and was very apparent during the appointment) but she had no explanation. 

A week later she had her next seizure and was then started on epilepsy medication. An MRI found diffuse cerebral microhemorrhage but why we did not know. The neurologist again wondered if it was a byproduct of her heart surgery and time spent on the heart-lung bypass machine. Each seizure was associated with a temporary loss of skills. She lost the ability to sit up, her hand movements were uncoordinated, she showed no interest in play, and was too fussy to eat so we sadly reverted back to tube feeding. The only thing that brought her comfort was being held for hours on end. After starting her first anti-epileptic medication, her fussiness subsided somewhat but she still wasn’t her old self. She’d make sudden jerking movements or her head would bob up and down while she zoned out. Full blown unresponsive seizures continued and gradually became more frequent, clustered, and prolonged. She went into status 7 times. We were given rescue medication to administer but it was ineffective. Her meds were increased several times and a 2nd medication was added. We became accustomed to dropping everything in order to rush her to hospital. She had a growing collection of cuddly toys from the many ambulance trips and children’s hospital visits. 

Each time we saw the neurologist, I left feeling like she played down the severity of the situation. I happened across a genetic epilepsy panel that Cleo was eligible for (thanks to a helpful parent in a FB group for parents of children with epilepsy). When I asked about it, however, the neurologist was dismissive and said “cases like Cleo’s are almost never genetic”. The prolonged nature of the seizures, however, were unusual (most seizures are well under 5 minutes long), her seizures seemed to be mixed in type, which again is less common, and her fussiness and sleeplessness were striking (epilepsy meds usually cause increased sleepiness not the opposite). My thought was, what harm could it do to at least run the panel? After asking several times, begging even, she finally agreed. 3 months of seizures had passed by the time the test was ordered. 

The results identified 2 variants involving the antiquitin gene, both associated with PDE. I immediately looked it up. “PDE is often characterized by prolonged seizures with associated fussiness”. I knew we very likely had our answer even though it was an atypical presentation. I felt a sense of relief and hope. Diagnostic limbo is a very hard place to be, especially when your gut is telling you that something is very wrong. A urine test was ordered for alpha-AASA (we were not informed how to store the urine, i.e. to freeze it immediately, so it’s a small miracle that the sample even gave a positive result) to confirm the suspected diagnosis. As soon as pyridoxine was started, the seizures thankfully stopped and our beautiful, happy girl re-emerged from the fog. The first 24 hours on pyridoxine, however, were not smooth. Cleo became extremely disoriented as if intoxicated, could barely hold her head up, vomited repeatedly, and then sank into a deep sleep for 15 hours that was difficult to rouse her from (I did not sleep that night). 

At the time, we assumed it was unrelated as pyridoxine is just a benign vitamin (B6) and she’d recently started another anti-epileptic drug (AED) but I later read that starting this medication can cause transient cerebral suppression in infants with PDE and should be undertaken in an ICU setting. In retrospect, I wish she had been hospitalized and monitored but one of the pitfalls of a rare disorder is that often the medical team knows so little that they are not equipped to give adequate guidance. Fortunately, we’re now with a team that is far more aware of PDE even though Cleo is their first patient; we are part of the international patient registry and they are in close contact with another team in Colorado that has a small number of PDE patients.

We have successfully weaned Cleo off of the AEDs and she is now over 6 months seizure free. Once we were under the care of a metabolic geneticist, Cleo began arginine therapy, a strict low protein diet and medical formula. She was feeding orally by this point but refused the formula despite trying all the tricks so we had to tube feed it. As soon as we did so, however, her appetite dwindled and after 3 weeks she’d lost nearly 10% of her body weight. The levels of neurotoxins in her system normalized but her lysine levels dropped unhealthily low. In Cleo’s case, her off-diet lysine baseline is at the very bottom of the normal range (which is where they want it to be) yet her neurotoxic levels are still high so we are now trying to bring down her lysine a little below normal range so as to reduce the toxins without compromising growth. In short, it’s not easy trying to thread the needle. She’s currently on restricted lysine (16g protein / day) but not on the medical formula and is growing beautifully and taking all solids and liquids by mouth (we use the g-tube for her medications but that’s it). We may have to restart the medical formula in the future if her labs change. Cleo still has some delays but has done a lot of catching up since her diagnosis and starting treatment.

She’s 1.5 now, walks or runs everywhere and oh boy does she climb! Her most recent review found a significant delay in expressive language but otherwise her delays are mild, and she’s making great progress in speech therapy and has started to sign. Her story is yet to be written of course but I think there will always be a question in my mind of “how would things be different had we known about PDE at birth?”. At the very least, I imagine we could have avoided the feeding tube and had a much more normal first year of life. Raising twins was hard but raising a child with a rare, undiagnosed metabolic disorder was a whole new level of hard and quite isolating. Watching her go through open heart surgery was nothing compared to helplessly witnessing her in a state of metabolic encephalopathy. Children with a later onset of seizures tend to fare better than those with classic PDE but the length of diagnostic delay is also a determiner of developmental outcome. There is so much that is still unknown about this condition, such as why some children start to seize earlier than others or why some do better than others (Cleo’s antiquitin enzyme is completely lacking yet she has fortunately had a relatively good outcome so far, developmentally, for example). For that, we are extremely grateful. Her extremely happy and social demeanor despite what she’s been through reminds us daily that we are very fortunate and honored to have Cleo as our daughter. She is such a happy and resilient little girl!

Libby
enhopton@gmail.com
Hillsboro, OR