Published by
Stanford Medicine

Genetics, Pediatrics, Research, Stanford News

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

16 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

  9. ashleigh Says:

    Have you asked your doctor to have your son tested for autism?

  10. anthony Says:

    I’m 31 I have the same issue this info was helpful

  11. Rebecca Says:

    My daughter will be 5 this year and never had a single drop they go glassy looking and red when she is up set bit never a drop I’ve gone to doctors about this and still no result I can’t find anything online about it I just don’t know what to do I don’t want pepole to think she is heartless because of it.

  12. sheralee Says:

    my son is a twin he has a twin sister they are 33 months old …. we live in the uk .. and our system is not good in our local area i feel im wastin my time with everything they were born at 33 weeks my son was twin A born first it took 12 minutes to get him to breath in nicu 3 weeks ng tube fed has sever reflux even now .. there placentas had joined causing ttts so he was very yellow up to 14 weeks as took too much nutrients and made him self poorly .. he had a operation last august to probe his tear ducts and a operation due this august to cut and tighten his eye mucles his eys have a 45% drift at the moment .. he has global development delay .. he is waiting for speach and language appts he has anxiety he has had repeat numerous genetics tests LACTATE…HB/FULL BLOOD COUNT..COELIAC SCREEN..FERRITIN ASSAY.. CK CREATINE KINASE/CPK..AMONIA… and waiting for nect appoinment to have it re done again each time the results come bk anaemic.. creatinine kinase is on the outside range … and amonia lactate on outside range .. his right side isnt as good as his left side at 1yr 2 days he managed to sit unaided.. he crawled in a sniper manner using one side and dragged the other side .. now if he walks he hobbles and his one legs gives way .. any ideas as to what the paeds are looking for or what is wrong … paeds say we will just keep repeating the tests every 4to 6 months with no reason or explanation .. im going out of my mind now his G.D.D age is 18 to 22 months in all areas he is 33 months now like to know what people think as im bashing me head off a brick wall not knowing what the out comes could be .. id like to know worst and best outcome as im a strong willed minded person .. and like to prepare myself for what could be .. he still does not cry even haveing canulas placed in his hand taking 12 vials of blood not a tear but he will scream untilll he is physically sick ??

  13. Aleeta Says:

    My 5 1/2 year old son was diagnosed with apraxia at age 3 1/2. He also has never been able to cry tears. Are they doing any new studies?

  14. Audrey Says:

    My daughter a was I’ll for year.It started with no tears…weakness. ..speech issues…and vomitting. She is shy of about one and a half years being diagnosed with allgrove syndrome or also known as triple A syndrome. It is a genetic problem. Only two labs check for this genetic problem. See a endocrinologist and genetic doctor. I must warn you due to its rarity they may not even know what you are talking ny try methodist hospital

  15. Sandra Says:

    I’m 65 years old and while I have cried many many times in my life, I have never shed a single tear. I have an older sister who cries buckets of tears, a brother 13 months younger than me who cries but doesn’t shed tears and another brother 30 months younger who also cries tears. Myself and brother #1 both share this problem. We were separately diagnosed as having Sjogrens, sensory/motor peripheral polyneuropathy and familial tremors. We are not diabetic. We both have extremely dry eyes. My brother has had eye plugs but it did not help. When tested, my eyes are severely dry. It is my understanding that the common medical conclusion is that it is not possible to cry without tears yet I have lived my entire life without crying with tears. I cry and sob but never have never shed a tear. My brother had some slight learning issues in school but no social issues and I was highly functioning and social, an “A” student in school. I have always had a difficult time coping with emotional issues, however. Loss is more difficult for me than my siblings.

    I had always believed the reason I didn’t cry tears when I cried is because of my chronic dry eyes from Sjogrens Disease. I was surprised to learn that dry eye is not the same as not crying tears. As a child I wonder if I developed a physical way to show I was crying because I could not cry tears. My Mother had her hands full with 4 children just 3 1/2 years apart in age so she may not have noticed my lack of tears. I remember being told I was faking when I cried at a young age. I make a crying noise and wrinkle my face but wonder now if I am really crying or is it possible my brother and I could have a form of this gene defect? During therapy, my psychologist, who knew I did not cry tears, saw me cry without tears on many occasions. I would be happy to hear from someone and provide additional information if you believe my situation is relative.

    Thank you.


  16. Maya Rowe Says:

    I’m 37 I live in Hobart Tasmania I have Aspergers Syndrome and Dyspraxia ive never been able to shed tears and I’ve never really looked into it


Please read our comments policy before posting

Stanford Medicine Resources: