She's so small. That was my first thought when I first saw Marian, like a miniature porcelain doll.
At Marian's early well baby visits her weight gain left something to be desired. It took her several weeks to hit 7 pounds and at Thanksgiving, when she was three months old, she only weighed 8 pounds.
Marian on Thanksgiving weekend, weighing in at 8 lbs
At Marian's 6 month visit she wasn't sitting up. The doctor pulled her from laying down to sitting and her head lag was appropriate. When tipped Marian knew to put her arm down to support herself, but she had almost no core strength. Marian did impress by saying a garbled "hi" to the doctor at this visit which was exciting. Her weight percentile was low, in the 3 - 5th% range and she also wouldn't bear any weight on her legs.
At 8 months I called our pediatrician as Marian still wasn't bearing weight on her legs or sitting steadily, she also was having trouble transitioning to solid foods. With her support I called Regional Center. The physical therapist evaluator right away said Marian has hypotonia or low muscle tone - something we'd noticed since birth but hadn't known what to call. It's not a condition but a symptom of an underlying problem - ranging from harmless to very serious, often the cause is unknown and not significant. I remembered a video of myself in ice skating lessons with my legs wobbling like overcooked spaghetti. It must run in the family I thought, relieved. She recommended we talk to our pediatrician about whether to see a neurologist.
Around eight months old, Marian used her hands and arms to provide extra support to compensate for weakness. You can also see Marian's enlarged belly from her spleen, although we didn't recognize it at the time
Marian was 9 months and could sit for just a minute before toppling over, note the pillow
At this time our beloved pediatrician retired and we had to quickly pick a new pediatrician and make it a good one. We met our new saving grace pediatrician for the 9 month visit. She took one look at Marian and said she has a sweet spirit, which of course she does. Very insightful right off the bat. She wasn't overly concerned about Marian, but did agree she has "mild to moderate" hypotonia and she could see a neurologist as "an aggressive move," just to make sure. I agreed. She also ordered a slew of labs including a liver panel, CBC, thyroid, lead, etc.
The next week, around May, we went to the neurologist, Dr. A, for the first time. I was sick with worry about what she would say. She was overall reassuring but was clear there were many many things that could be causing this, some harmless, some not so harmless. She ordered a CK test (more labs) and said she'd see Marian monthly. If after a few months she wasn't improving she'd order a MRI. I started my question routine. Are there signs of anything degenerative? Nothing that jumps out right now. She recommended Marian start PT right away, as much as possible.
We called a PT clinic through insurance and were told it would be a three month wait for services. In the interim of waiting for Regional Center, we paid privately for physical therapy twice a week.
Starting physical therapy with Katie at PEAK Physical Therapy at 9 and a half months, Marian didn't bear weight on her legs and couldn't lift her hips off the ground
A few days later we got the test results (ok I obsessively called the office every day) with Marian's CK level: it was low. This was good in the sense that it wasn't high as that would have been a strong indicator for one of the muscular dystrophies. But low CK levels are unusual and doctors generally agree it can point to a problem with muscle mass and/or strength.
In June, I was thrilled with Marian's progress after starting PT, the doctor not so much. She examined Marian and suggested trying to give her more protein to see if that helps the CK level. She said not to worry about the CK now and it could be a lab error, she reordered the test. The MRI that she had previously said we'd talk about in a few months, well, that one she thought we should order now. Oh yes, and there's one other test a microarray to check the number of chromosomes, might as well order that now, too (this came back normal). I asked my question again, does Marian show signs of anything fatal or degenerative? The answer this time made my stomach drop: we'll have to wait and see what the MRI shows.
In July I went back to the neurologist with Emily and Marian, our trio of chaos, the CK came back low again. I can't even tell you how much Greek yogurt I'd fed Marian to try and bump it up. I tried to get Marian to show off her new skills of bearing weight on her legs and pushing from the ground into a supported sit when I placed my hand on her hip and put pressure. The doctor was encouraging but also referred us to CHLA to see their neuromuscular specialist due to Marian's low CK and slow growth/weight gain. Dr. A said Marian might have a congenital myopathy - a genetic muscle problem, ranging from mild to severe. I asked her, pressing her always, it's in my nature - where do you think Marian will fall? No way to know, her guess would be mild to moderate. Can we rule out something degenerative? No.
After a couple months of PT Marian could push up into a sit, was bearing weight on her legs and could sit steadily for long periods of time without compensation
In August, just before Marian's first birthday, CHLA offered us an appointment with Dr. C, a pediatric neurologist, a few days before her scheduled MRI. Dr. C was like an angel. She took an extremely thorough history and did a lengthy physical examination. I kept jabbering at her about what is wrong, and rattling off Marian's skills, and can we please just rule out something degenerative already? Marian started to fuss and I was juggling soothing Marian, thinking of questions, and processing the information all at once. So, when Dr. C said, "I think I can feel her spleen and liver and I'd like to order an abdominal ultrasound to check this, " I said: ok. Later when I told Paul about this, he asked, but what could cause that? I had no idea. But it was important, for better or worse. Dr. C also wanted to add on an abdominal MRI and MRI of her femurs/legs to check the shape of the bones and muscles. Dr. C said she would call me the same day as the testing with results so we wouldn't be waiting in limbo agony.
To accommodate the lengthier MRI we lost our spot in radiology that was the next week. The nurse practitioner said they recommend doing one longer MRI instead of two shorter ones.
The next week it was time to bring Marian back to Dr. A for her monthly visit. Marian was sick with croup. We had been at the emergency room with her earlier in the week when she couldn't stop coughing for ten to twelve hours. She was fine at home but when I got her to the neurologist, alone of course, she started a terrifying coughing fit in the waiting area. I felt so embarrassed that I'd brought her out and like the world's most horrible mother. The neurologist called us back into her office and over the coughing very calmly said, Marian's spleen and liver being enlarged make sense and there are genetic disorders that effect the brain, liver and muscles. It will be difficult to diagnosis.
On September 14 I brought Marian to CHLA for her abdominal ultrasound. Marian did well with only some crying and lots of coughing as she now had bronchiolitis. Afterwards I headed home with Marian and waited for the results.
Dr. C called about 3:30 p.m., Marian was napping. Marian's spleen was about 11 cm and liver was within normal but at the uppermost limits. What does this indicate? It indicates a storage disorder. Something I'd barely heard of. What does this mean? Some of them are progressive, some aren't. Some are treatable....and some aren't. What was left unsaid, hanging in the air: fatal. More testing needed. I called Paul crying and we read together what the internet has to say about storage disorders, it was very bad - reading that of the lysosomal storage disorders, they were almost all fatal by early school age.
In fact, 95% of storage disorders don't have treatment. NPC is a kind of lysosomal storage disorder. 1 in 8,000 babies are born with a lysosomal storage disorder and they are all fatal without treatment. And only 5% have treatments. The odds were not in our favor.
Later that week we saw our pediatrician who gave us an extra long appointment, I cried in her office. She ordered more tests for Marian, re-testing her liver panel, CBC, and adding CMV and Epstein-Barr which are both viruses that can cause an enlarged spleen. I also asked her to refer us to a GI and geneticist at CHLA which she did right away. I called UCLA and got an appointment with a hematologist, as Marian has thalassemia minor anemia which is from my maternal side of the family and I hoped against hope that could be the cause of the enlarged spleen.
The blood work came back with some hope - the CBC showed a high white blood cell count, the liver enzymes were elevated - but that could be normal from a virus, and she did have CMV - which can cause an enlarged spleen. To make matters even better, we went to see a hematologist at UCLA who could easily start a cult he was so calming, who said the thalassemia wouldn't cause many of Marian's issues - but it could cause an enlarged spleen. Hope.
I took Marian for her blood work ordered by Dr. C, they ran a lysosomal storage panel (which does not include NPC), Spinal Muscular Atrophy, Pompe Disease and a Congenital Myopathy panel. I sat typing these tests into my phone looking for which one to root for: answer, none of them. They're all horrible. At this point I had come across Niemann Pick Type C online and started asking the doctors about the possibility of Marian having it. The literature for NPC says it needs to be diagnosed through a skin biopsy, an invasive test if you're not sure. There's actually a blood test that can diagnose it now, but the literature is in the process of being revised.
I took Marian to a GI in Pasadena while waiting for CHLA to get her in with a friend. I asked: is there anything other than a storage disorder that could be causing her spleen to enlarge? Answer: yes, a mitochondrial problem. I said: is that serious? And the doctor looked at me like he knew I copied my lab partners homework in biology. He skipped a beat and said: yes. He then said but don't look it up. He had good ideas of what to pursue for Marian and ordered more labs to screen for mitochondrial issues. FYI I did look it up and you do not want your child to have a mitochondrial issue.
I took Marian back to the lab for about 6 more blood tests, a urine sample (that's fun) and stool sample. All these tests came back in the normal range.
In the midst of the medical stress Marian continued to make great progress in PT, taking first steps with support here at fourteen months
In October we saw Dr. C, who stayed in very close touch with us in the interim, between the thalassemia, CMV and Marian's slow but steady progress we were feeling hopeful still. I showed Dr. C how Marian was "cruising" - basically bearing weight on her legs, white knuckling clutching a chair and would take a tentative step if I shifted her weight at her hips. It was cruising. Dr. C said she was leaving for a new hospital but she had already spoken to Dr. D, the neuromuscular specialist at CHLA, who was accepting Marian's case. She also put an order in for an EMG to test the nerves and muscles in Marian's legs and arms.
A couple weeks later Marian's blood work came back with good news, the lysosomal panel was negative - which included a screening for Gaucher, Niemann Pick Types A and B and a dozen or so other lysosomal storage disorders. In fact everything was normal except she is a carrier for one recessive gene of a congenital myopathy called nemaline rod. Dr. C said, "could Marian end up being fine? Yes, it's possible. But I still think there's enough here to warrant a full work up to check." Somehow she was able to say this in a way that only made me like her even more.
In early November we brought Marian to CHLA for her EMG. We got to meet Dr. D which was like meeting a legend in person, we immediately knew Marian was in good hands. She did the EMG and placed wires and needles into Marian's arms and legs sending electrical pulses. I said, "I think Marian is going to throw up," Dr. D said kindly, "it's ok I have a change of clothes," and then Marian threw up all over Paul who was in his work clothes. No change of clothes for dad. The results of the EMG came back normal, which ruled out a few conditions.
Dr. D talked to us about Dr. E at Cedars Sinai, a neurodiagnostician, who could possibly consult on Marian's case. We were thrilled with the possibility. In the mean time, I spent my free time harassing the genetics department at CHLA from the referral issued in September.
In late November we got in for our clinic appointment with Dr. D who gave us the most detailed information we'd received thus far. She had already followed up on referring us to Dr. E. In early December I went with Marian and a friend to see Dr. E at Cedars Sinai who did another thorough history. He also got the ball rolling to do the test that ended up diagnosing Marian, the DNA Whole Exome Sequencing.
Whole Exome Sequencing tests the exome, which is about 1% of the DNA but contains a mini version of the other 99% of your DNA. The test could not pick up everything, but if there was a genetic issue - any genetic issue - it had about a 50 to 85% chance of picking it up. It would take 8 weeks to come back, once drawn. If the Whole Exome Sequencing came back normal the plan was a muscle biopsy and skin biopsy next.
Dr. D and Dr. E also talked to us of the possibility of a mitochondrial problem, storage disorders as well as congenital myopathies. Even though Marian's mitochondrial screening came back normal she could still have it.
Emily and Marian in November 2016
From here things moved very quickly diagnostically. I kept asking my question: can we rule out something fatal or degenerative? The answer: no. But yet, it also didn't jump out as extremely likely. Typically, but not always, there would be more symptoms by this age. Typically, but not always, with degenerative diseases there is muscle stiffness, not muscle weakness. There was some hope in that. Dr. D pointed out Marian is weak in her hips and shoulders, something very typical of a myopathy or muscle issue, which held hope of a normal, healthy life possibly. Ok I thought, great, so does that rule out a storage disorder? Answer: no, because some myopathies are also storage disorders. Paul and I would argue over her exact words when we got home - me with a negative spin and him with a positive. I called her one day and asked her to repeat an answer to a question so I could transcribe it word for word to read it over and over again. It wasn't very encouraging for Marian skating through without something serious going on. She was very kind and patient with me and is an incredible doctor.
Just for kicks during this time we also went to see an Infectious Disease specialist at UCLA per our pediatrician to see how CMV fit into the equation. The result, it doesn't. Marian's AST and ALT, two liver enzyme levels, had been mildly elevated since September. The ALT bounced between normal and mildly elevated but the AST was consistently a bit high. At this point in time, this was not being caused by CMV.
Here comes early December and her spleen was still enlarged. I could feel it when I would press on her belly. I tried to measure it at home. I'd stare at it as she moved around the room wondering what is happening in there. We tried taking her off dairy. Tired cutting down on gluten, hoping that was the cause. Saw a naturopath, reflexologist, pediatric chiropractor.
After a lengthy process we got in with CHLA genetics in early December. I went with Marian and my friend's mom. Marian batted her eyes at the geneticist and was all smiles for him. I asked my question with the same answers. Except: could it be NPC? Yes. But it could also be other things, too.
Marian's spleen and liver were still large in examination. He measured her chest, her ears, her legs, checked the movement of her eyes, checked inside her mouth all with a one year old trying her best to flirt with him. She got a good report physically. Let's see what the testing shows. Whole exome is a good idea and get it done right away. I walked out of the meeting feeling sad, my friend was encouraged. I wondered if I was going crazy reading things in that weren't being said?
I took Marian back to the CHLA lab in Arcadia for the latest round of tests - FYI this is the very best lab to have dozens of vials of blood drawn from your baby, they're amazing. The geneticist ordered a very thorough screening of different enzymes and screening tests, I think he tested for about a dozen plus things. They all came back normal.
On December 23, 2016 Marian finally had her MRI, it would take 2 1/2 hours and image her brain and the top of each leg. We got the results Monday morning December 26. I was in the Whole Foods parking lot when the doctor called. The MRI of her brain showed a thin corpus callosum and decreased white matter volume. This could be from a range of things, including some storage disorders and mitochondrial disorders. Or it could be from lack of oxygen, even very brief, during birth. It's considered non-specific. A pretty non-horrible result in the world of possibilities. It did rule out a few storage disorders. Possibly Marian has a partial gene expression of a storage disorder or possibly a myopathy plus a mild mitochondrial issue or possibly a straight up storage disorder. What is the prognosis I asked? Still unknown, can't speculate, let's wait for the whole exome sequencing labs which were to be drawn soon. For the MRI of her legs it was complicated. Possibly showed some dying tissue in her legs. The radiologist thought she might have a fatal and untreatable viral muscle infection, but it's unclear. This would definitely show in the labs.
Next step: emergency rush visit to CHLA Arcadia lab to re-check CK, inflammation levels, autoimmune panels, muscular dystrophy panels, etc. If anything came back elevated would do an emergency muscle biopsy right away. If everything came back normal then would wait for the exome sequencing results and do the muscle biopsy after that. The tests came back a couple days later, all were normal.
Christmas morning, waiting between the MRI and the results
On December 30th we got Marian's blood drawn by a mobile lab technician for the whole exome sequencing. It is a $20,000 test if not covered by insurance and it took a few weeks to get insurance preauthorization. Once the blood was drawn we just had to wait six to eight weeks to see what it would show, if anything.
On January 3 I took Marian back to CHLA for another ultrasound. We were hoping it would show a reduced spleen and liver size, but of course if didn't. Both still enlarged, the liver was stable and the spleen was 1 cm larger - about the size of a ten year olds.
The next day I brought her back to the UCLA hematologist who said he didn't think the anemia would cause the elevated liver enzymes and enlarged spleen at this size, and it was outside of his expertise but a storage disorder was a strong possibility. My aunt Anna was with me. I teared up and said, but are there any storage disorders that aren't fatal? The answer: yes, there's a range. But which ones I asked, which ones aren't fatal? Unsure. My aunt bought me chocolate on my way to the car. I felt shell shocked. I emailed Dr. D and Dr. E, I wanted to do the skin and muscle biopsy.
We were waiting to see what the Gene DX whole exome sequencing would show. Since Marian was stable and still making progress all agreed it was better to go step by step. As a back up plan I called the Mayo Clinic and got information about how to get Marian in there to see a panel to try and reach a diagnosis. I had a very strong feeling time was of the essence. I gave the Mayo Clinic some preliminary information and they said we had to collect all her records to get an appointment. I went to CHLA and filled out the records request and started getting it organized.
More blood tests drawn to prepare for a hematology appointment.
In February we got an appointment with a hematologist at CHLA, my friend Sudarsha went with me. Marian's doctors wanted a second opinion for hematology and it made sense to move her there so all the info could be in one system. The hematologist showed me how to feel Marian's spleen and liver myself. Her liver was quite enlarged from a manual exam. This was devastating. A progression. Her blood work also looked more unusual than just thalassemia anemia alone. The hematologist suggested a liver or bone marrow biopsy, he suspected a storage disorder. The biopsy wouldn't say definitely which storage disorder but would confirm that there is a storage disorder. I choked out trying to not cry, "is she going to die?" He said there's nothing that would indicate that any time soon, she's very vibrant, healthy and making progress. I felt like my throat closed up and said, "but aren't storage disorders fatal?" And he said something like there's a range, and I said, "but which ones, which ones that effect babies aren't fatal?"No answer still.
I walked out and bumped into Marian's GI who agreed given the progression of the liver size we should do a liver biopsy ASAP. I emailed Dr. D and Dr. E and they also agreed to do a liver biopsy ASAP since there's been a change. On my way to work after the appointment I was talking to my sister-in-law and the Mayo Clinic beeped over on call waiting and offered us an appointment for March 10, 2017. We took it.
On February 28, 2017 the results of the whole exome sequencing came back, positive for NPC. Fatal.
And that is how we got the diagnosis.
March 10, 2017. Meeting Dr. Patterson at The Mayo Clinic. Hope that NPC has been fatal in childhood in the past but may not be for this generation
We shared Marian's diagnosis and launched the GoFundMe from our hotel room at The Mayo Clinic. Marian smiling at a future that was looking a little bit brighter.
#diagnosis #parentingfears #raredisease #NiemannPickTypeC #NPC #NPC1 #grief