A metabolic crisis can manifest differently across various genetic and metabolic disorders. Even among patients with the same metabolic condition, not all may exhibit the clinical symptoms or laboratory findings typically associated with a metabolic crisis. What does a metabolic crisis mean for families affected by TDD? For those who have experienced it, what symptoms did they encounter?
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Our daughter is 30 years old and received her TDD diagnosis in 2022 when she was 27 years old and had just experienced her first metabolic crisis. She has had “spells” or what we previously called episodes of ataxia, slurred speech, drooling all her life, but the metabolic crisis/decomposition was different from the episodes/spells. Her crisis was the culmination of three months of poor health that included the reemergence of the spells, which she had not had in many years; extreme but vague “discomfort” that we now know was severe constipation and angry mood. Blood work showed high liver enzymes: ALT was 133 (normal is 100) and AST was 98 (normal is 25). The day before the crisis, she had a seizure (she had not had one in over a year) and then the next morning she woke up very lethargic, unable to hold her head up, vomiting, unable to walk or talk - very low energy. We took her to the ER and she was eventually admitted to an observation floor but not given any IV fluids so she continued to decompose and became “catatonic” - for another 24 hours. When it was discovered that she was in status epilepticus and lab results showed lactic acidosis (pH 7.15 and lactate 5.5) and she was experiencing SVT (super ventricular tachycardia) and mild fever she was transported to the neurology ICU and given multiple boluses of lactate ringers, Ativan, intubated, started on metoprolol, but continued to deteriorate. Her providers did not know what was wrong with her. She continued to have a run of SVT (irregular heartbeat), sinus tachycardia, and experienced a pulseless ventricular tachycardia and received a defibrillation and synchronized cardioversion and amiodarone. She also had septic shock and a 3-hour run of intermittent hemodialysis. After a day in the Neurology ICU and visits from many specialists a pediatric biochemical geneticist was asked to help and she suspected Tango2 Deficiency Disorder, ordered whole genome sequencing and two weeks later we had the TDD diagnosis. Our daughter was in Neurology ICU for 11 days, the step-down Neurology unit for another 25 days recovering and 20 days in inpatient rehabilitation for a total of 56 day inpatient stay. She is now healthy and on a mito cocktail that includes her B vitamins and has been healthy, spell-free and no metabolic crisis in the almost three years since.
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Do any of you have any feedback for Dr. Lina Gonzalez about what “crisis” means to you?
I wish I could provide more details about Robert and the crises he went through, but since his diagnosis was only made after his death, I’m unsure whether these were truly crises or simply episodes. Given that he passed away, I lean toward thinking they were crises. Robert’s episodes seemed to begin shortly after his second birthday, and looking back now, I realize they started about three months after we took him off the 1-year-plus formula. I now wonder if those vitamins in the formula, which we later learned are beneficial for TDD patients, might have been helping him.
Robert also had 22q and was a silent aspirator, which caused feeding issues. He underwent a Submucous Cleft Palate repair at 12 months. The first significant episode occurred on April 30th, 2012, and I had shared the details in a 22q group at the time, which is why I remember them so clearly. Tango2 wasn’t discovered by the scientific community until 2016, and Robert passed away in 2015 at the age of 5. Here’s what happened that day of his first episode:
April 30th, 2012:
I noticed the following symptoms and called Robert’s pediatrician:
• After being awake for about 1.5 hours, Robert seemed extremely tired around 8:30 am and had some right-side weakness. He was wobbly and leaning to the right when sitting, and I noticed drool coming from the right side of his mouth.
• I put him down for a nap at 9:00 am, and he woke up around 10:00 am, looking a bit better.
• However, by 12:30 pm, his symptoms worsened. He could no longer walk or sit without falling and exhibited what seemed like stroke-like symptoms.
• At the pediatrician, his neuro exam showed normal pupils and tone on both sides, and everything seemed the same.
• By this time, Robert was hungry and eating.
• His left ear was fine with the tube still in place, but the right ear tube couldn’t be seen due to pus and bulging.
• The doctor concluded it was a severe ear infection causing vertigo, and two antibiotics were prescribed. By the next day, Robert was still weak but showing improvement.
Over the next three years, Robert continued to have episodes involving weakness, fatigue, ear infections, and ataxia-like symptoms. Rest seemed to help, but we didn’t realize that food or snacks were also beneficial until later.
We had been visiting Duke University’s 22q Clinic since we live in NC but In June of 2015, we started seeing doctors at CHOP’s 22q and You clinic in Philadelphia. At that time, Tango2 hadn’t yet been discovered. Our last visit to CHOP was in August 2015.
• We first visited CHOP in June 2015, where we saw Donna McDonald-McGinn, a genetic counselor and director of the clinic. While we were there, Robert had a “staring off” episode, and Donna advised us to go straight to the ED. There were no signs of a seizure when we got there, and Robert returned to normal shortly after.
• During our annual July beach trip, Robert experienced multiple “staring off” episodes. When we couldn’t get his attention, I contacted Donna, and we went back up to CHOP within two days.
• At CHOP, Robert had a 4-hour MRI, and because he had to fast beforehand, we found that his blood sugar was dangerously low at 35 when they tried to wake him up for 2 hours from the procedure. After glucose was administered, he woke up.
• Donna admitted Robert to CHOP for two days, but they couldn’t replicate the low blood sugar. She had blood samples sent for analysis to a research project she was aware of in Europe.
By August 2015, we returned to CHOP for another check-up.
We returned home to NC:
September 10th - 14th, 2015:
• On the evening of September 10th, Robert wasn’t feeling well. He was congested and clingy, and though he threw up some mucus, it didn’t seem concerning. I texted our pediatrician, and we planned to see him the next morning.
• Robert slept with us that night, and around 2:30 am, he woke up fussing, but I managed to get him back to sleep.
• The morning of September 11th, I tried to wake him around 7:15 am. I heard a gurgling sound and found he was unresponsive but still breathing. We immediately called 911. When the EMTs arrived, Robert was limp, unresponsive, and struggling to breathe, with an oxygen level of 80 and a blood sugar of about 50 (it dropped to 40). They gave him glucose, and his condition improved slightly. However, he did not regain consciousness.
• In the ER, they intubated Robert, did a CT scan (which came back normal), and started antibiotics and heart medications, suspecting he had a virus and was septic.
• By September 13th, after 12+ hours off sedation, Robert’s condition hadn’t improved. A second CT scan revealed almost no brain activity.
• On September 14th, after being taken off life support, Robert passed away.
These episodes and his sudden decline were incredibly difficult, and looking back, it’s heartbreaking to think that we may have missed warning signs due to the lack of a clear diagnosis at the time. I also wish we could have taken better notes so that we could pass on more detailed information.
Although Robert’s death certificate states that he passed away from sepsis, we now believe that his death was likely due to a hypoglycemic event, given the extremely low blood sugar levels found when he was discovered unresponsive. We’re also unsure whether he may have experienced a cardiac arrhythmia.
Tango2 Diagnosis:
On March 2, 2018, Donna from CHOP called to inform me that researchers in Poland had discovered Robert was missing the Tango2 gene, and that his father is a carrier. This meant that Robert’s 22q diagnosis served as the second copy of the gene difference. It took three attempts to analyze his sample before the deletion was identified, as it was very small.
Hopefully this information is helpful, as I’m not sure if it is what you are looking for.
With our daughter, Ellie, the first sign of crisis was constipation. After having a cold virus in early December of 2016, she went several days without a bowel movement and her muscle tone got very high, to the point she looked like she was in pain. We took her to the ER, where they administered an enema, and after two large bowel movements, she seemed like she was getting better.
While we were at the ER, they did blood work and she had elevated cK levels, but it wasn’t anything that threw up a red flag. TANGO2 hadn’t been identified yet and we didn’t know to look for that sign.
We went home and were there for about a week, but Ellie seemed to progressively get worse. Her muscle tension continued to increase and started getting more immobile. When we woke up Christmas morning, she wouldn’t move her body at all. We got in the car and drove four hours to the ER we had been at before. They immediately admitted us and started checking her. The first thought was sepsis, but she wasn’t showing any of the other signs. They continued to check her and when they cathed her, her urine looked like iced tea. They immediately identified it was rhabdomyolysis. After further bloodwork, her cK levels were off the chart.
It was a long two months she spent in the hospital, but she fought back and regained her skills.
Elevated cK levels are a sure sign for us. We have learned that regular bowel movements are critical for her. If she goes a couple of days without one, we will use a suppository. Her muscle tone increases when she is constipated.
When he was 2 years and 3 months old, Yuito had a metabolic crisis. He didn’t eat much dinner the night before and went to bed early. He woke up around 6am, but he seemed sleepy so he went back to sleep without eating anything. He woke up at 9:30am . He had been fasting for about 15 hours.
Immediately after getting up, he collapsed to the side, his eyes wide open and stiff. Even when I held him, his whole body was weak and foaming at the mouth, and he was having convulsions so I called an ambulance right away. He continued to have convulsions during the transport, and he was in a status epilepticus.
An hour later, we arrived at the hospital and gave him anticonvulsants and started various tests. His blood sugar was low and no other major changes were found in the initial blood test. CT and cerebrospinal fluid tests were also fine.
Later in the evening, his blood CK and liver function were worsening, so he was transferred to a more specialized hospital. I heard that he was being treated with vitamin therapy for acute encephalopathy.
He was treated in the PICU, regained consciousness, was able to eat, and was transferred to a general ward. Due to the effects of rhabdomyolysis, I was bedridden, but with rehabilitation I was able to walk again in about a month. However, I started having epileptic seizures.