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Crying without tears unlocks the mystery of a new genetic disease

Crying without tears unlocks the mystery of a new genetic disease

LittlePackardGirlSometimes one tiny clue holds the key to a baffling medical mystery. That was the case for a San Francisco Bay Area child whose family and doctors struggled for the first three years of her life to pinpoint the cause of her developmental delays and neurologic, muscle, eye and liver problems. The essential clue? Grace Wilsey doesn’t make tears when she cries.

Grace’s combination of symptoms didn’t fit any known condition. Her team of caregivers at Lucile Packard Children’s Hospital Stanford, led by pediatric geneticist Gregory Enns, MB, ChB, strongly suspected that she had an as-yet-undiscovered genetic disease. Several genetics experts at Stanford helped sequence her genome, then came up with a list of eight mutated genes that might be responsible for her symptoms. They ranked the genes in order of likelihood that each was involved and began working down the list to try to pinpoint the culprit.

At the bottom of the list was a gene called NGLY1, which normally codes for N-glycanase 1, a housekeeping enzyme that helps cells break down and recycle mis-folded proteins. Part way through the investigation of the list of eight suspect genes, Grace’s parents, Matt and Kristen Wilsey, contacted a team at Baylor College of Medicine that had also previously performed whole genome sequencing on Grace and consulted on Grace’s case. A postdoctoral associate there, Matthew Bainbridge, PhD, reran Grace’s raw sequence data against the latest algorithms. NGLY1 jumped to the top of the candidate list of what was causing Grace’s underlying condition. As a next step, Dr. Bainbridge searched the scientific literature and found something so new that the Stanford researchers hadn’t yet run across it: a report of one child with suspected NGLY1 deficiency. From our press release about the discovery:

Bainbridge read in the medical literature of another child, studied at Duke University, whose caregivers there suspected his unusual symptoms were tied to an NGLY1 gene defect. But without a second patient for comparison, they weren’t sure.

As part of his detective work, Bainbridge emailed Kristen Wilsey to ask if Grace produced tears when she cried. Wilsey replied that although Grace’s eyes were moist, she never really made tears. Bainbridge wrote back, “I think I have it.”

“My heart jumped out of my chest,” Wilsey said. The first patient identified with NGLY1 deficiency, it turned out, also did not make tears, and the same characteristic has since been observed in seven of the eight children with NGLY1 gene defects whom the researchers have identified.

The scientific implications of the diagnosis are profound: Researchers can start looking for treatments or a cure. So far, the way that malfunctioning N-glycanase 1 causes the children’s symptoms is not understood, so unraveling the connection is a large area of focus for scientists.

They can also look for variants of the disease, Enns told me. “We are likely detecting the most severe form of NGLY1 deficiency – ascertainment bias – and it is quite possible that more mild forms of the disease exist,” he said. The first eight children found with NGLY1 deficiency are described in a new scientific paper publishing today in Genetics in Medicine; Enns and Bainbridge are both primary authors. Of the children, six have the same mutation in their NGLY1 gene and (probably not coincidentally) also share a very severe manifestation of the disease. Two children, including Grace, have different NGLY1 mutations and also have less severe disease, a finding that hints that other children with as-yet-unexplained developmental delays may also have less-severe variants of NGLY1 deficiency.

Unusually, it’s not just the scientists who are participating in the discovery process; families of affected children have also played an important role. Matt Wilsey is a co-author, with another NGLY1 deficiency father, on an editorial in Genetics in Medicine about their role, and the two fathers are featured in a podcast produced by the journal.

Beyond the science, the diagnosis has also had an big human impact:

“Before we had a diagnosis, we always had the fear of the bottom dropping out,” Matt Wilsey said. Without knowing exactly what was wrong, he and his wife constantly worried that Grace might suddenly deteriorate. “In that situation, you’re always on the defensive; you can’t enjoy parenthood,” he said.

“With a diagnosis, we can start working on a cure or a way to alleviate some of Grace’s symptoms,” Kristen Wilsey said. “It’s hard to describe that feeling. When we got the news, we were so excited that neither of us could sleep.”

Photo of Grace Wilsey by Katherine Emery Photography, courtesy of Stanford Children’s Health

8 Responses to “ Crying without tears unlocks the mystery of a new genetic disease ”

  1. Carolina Ortega Says:

    Hello I have a 15 month old baby girl who has never cried with tears and no doctors seems to be able to give as an explanation. However besides this symptom she hasn’t got any other. I was wondering if there is any way in which you could help me since I’ve always felt that her lack of tears isn’t normal.

  2. Joseph Woolf Says:

    How likely is it for someone to inherit the defect NGLY1 Gene?

  3. Erin Digitale Says:

    Caroline and Joseph, thank you for your comments.

    In response to Caroline’s question, Dr. Enns said, “I am happy to hear that your child does not have other symptoms of NGLY1 deficiency. Without other symptoms it is unlikely that she is affected by this condition. However, it is important that eyes are kept moist. If there is concern about keeping her eyes moist, an evaluation by a pediatric ophthalmologist would be a good idea.”

    In response to Joseph’s question, the overall population prevalence of defects in the NGLY1 gene is not known, but these defects are thought to be rare. Also, people who carry one defective and one normal copy of the NGLY1 gene are not affected by NGLY1 deficiency. It is only individuals with two defective gene copies who have the disease.

  4. Joanna Says:

    My son has a neuromuscular condition, vsd, gi issues, and doesn’t cry. I saw him cry once when he was 3, but it was a tiny amount of tears. He has been seen at Hopkins. I never mentioned this, but after reading this I think I maybe I should have. Even after he falls, no tears. He had a microarray completed. Nothing. He had a mri – normal. He had an EEG which showed some abnormal activity in the frontal lobe. He is always improving though. Is this something I should look into?

  5. Rebecca Says:

    My daughter is 8 weeks old. She has been in and out of the hospital since she was 9 days old. They say she has an undiagnosed metabolic disorder.They have ran numerous labs and her amonia is high her lactic acids and several others I can not pronounce.She has a variety of symptoms. She does not make tears and to be honest I dont think even for her age she sees. The hard part is she was delivered by a friend since I have my own problems so we don’t know much about her family history on the donner eggs side. She has seizure like activity which is never the same sometimes her whole body twitches, others she goes stiff and her eyes role, and sometimes she foams at the mouth. There are times she even quits breathing and we have to perform cpr. Our neurologist has referred us to see someone in genetics but that has not happened yet. Do you have any suggestions? Any advice at this point is better than no answers.

  6. Shannon Says:

    I am 25 years old and I have never shed a tear. I was always told that my tear ducts were backwards and ran in the back of my throat. I also was told
    that I inherited it from my great grandmother. I’ve never really tried looking any further into it because I didn’t even really know where to begin.

  7. Ashley Says:

    My son is about to turn 9 in a few weeks. He hasn’t shed one tear since he was born. His eyes do get alittle pink and kind of watery, but he doesn’t produce a tear. Alittle bit about his history…. He was a slow learner, he was extremely strong as a baby and toddler, he never made eye contact with me (or anyone), he lined all his toys up, when he started walking he tip-toed allot, he started playing with other kids when he was four, he would get really upset and angry allot, he wore certain types of clothes (basketball shorts or pants, not jeans). Four to eight years old- he doesn’t like going out after he comes home from school, he makes every excuse for us to stay home (he has an older sister) he makes straight A’s, he has lots of friends, he has a great memory, he notices what people wear (he can tell me what everyone’s socks or book bags look like ex.) he started getting tics at age 6. (He makes weird noises, his mouth opens, he srugs his shoulders, he tilts his head to name a few (they come and go) he’s very nervous allot, he gets his feelings hurt easily, he still gets mad and distant, he talks really loud (it’s like he cant whisper). I can go on and on.. doctors say that’s how boys act, he’s fine, tics come and go. I’m not one of those moms who takes their kid to the doctor every time they get sick or hurt, but I’m really concerned and have no clue where to go or what to do. Can someone please give me some type of answers.

  8. jan Says:

    Hi, my daughter is 4 years old and has never produced tears, her eyes have never been infected or dry but she has never had a tear when upset or hurt, I have been told not to worry but I cannot find information on it, it’s hard when she gets upset because it’s like she has no release she just gets angry because she can’t cry she is perfectly healthy other than this I’m just so worried it’s something more serious than just not having tears


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