Non-Ketotic Hyperglycinemia (NKH) is an inborn error of metabolism characterized by the accumulation of large amounts of glycine in blood, urine and, particularly, the cerebrospinal fluid (CSF). The metabolic block occurs in the conversion of glycine into smaller molecules. NKH is easily diagnosed based on plasma and CSF glycine concentration. Common symptoms include low muscle tone, lethargy, seizures, coma, apnea etc. The disease is inherited in an autosomal recessive pattern and is caused by mutations in the Glycine Cleavage System (GCS). ~85% of NKH causing mutations have been found in GLDC/P-protein and another ~15% have been reported in AMT/T-protein. NKH is a rare disorder and predicted to affect 1/76,000 individual. The current treatments, dextromethorphan and sodium benzoate (to neutralize the effect of glycine) have very poor efficacy.
Our research focuses on developing suitable cell and animal based models and therapies for treating these diseases.
Collaborator: Dr. Johan van Hove, UC Denver
Fiona and Friends
Fitzpatrick and Nohelty Familes
Our family became familiar with NKH (Non-Ketotic Hyperglycinemia) soon after the arrival of our third child, Fiona. She was born April 19, 2006. The pregnancy, labor and delivery were all normal and there was no reason for us to suspect that our Iives were about to turn upside down. It appeared that Fiona was healthy in every way at birth except the fact that she did not cry, open her eyes or move much at all. The very next day, she continued to be very sleepy, did not cry and they started doing some tests including an MRI. The EEG of her brain showed seizure activity and she was started on phenobarbital. As the hours went on, Fiona was unresponsive and she started having periods of apnea where she would stop breathing. On day three, Fiona was in a coma and on a ventilator. They continued to rule out possibilities that could be the problem and then we had to wait for the blood and spinal fluid tests to come back for a definitive diagnosis. The doctors treating Fiona emailed her MRI to Dr. Van Hove in Colorado who was the main doctor in the USA at that time who had been researching NKH. After looking at her MRI, he was very certain that she had NKH. The next day, her tests came back positive for abnormal high levels of glycine in her blood and spinal fluid and she was diagnosed at 9 days old with NKH.
We were told that Fiona would have severe developmental delays and not be able to do anything for herself. She would have difficult to treat seizures all her life, would not be able to eat and would have low muscle tone and not be able to sit up, crawl or walk. They suggested taking her off the ventilator and let nature take its course. We chose to start treatments for NKH which consisted of giving her Sodium Benzoate, Dextromethoraphan, anti-seizure medications and an antacid to combat the harsh effects of the SB on her stomach. We understood that there was no cure but we had to give our daughter a chance.
Within a week of starting treatment. Fiona opened her eyes, got off of the ventilator and was breathing on her own. We then had a feeding tube surgically inserted so that Fiona could safely be fed and through which we could administer her medications. After 28 days in the NICU, Fiona was discharged home with hospice care.
Fiona was finally able to meet her 2 older siblings, Karter & Maggie who were 3 ½ and 5 years old at that time. We then met with a geneticist at UIC and he told us that because Fiona had the feeding tube, she would make it past the 3 month old mark but that she would most likely not see her 1st birthday. Our lives now consisted of never ending Dr appointments (geneticist, pediatrician, neurologist, gastroenterologist and nutritionist). Hospice visits from nurses, social workers, art therapy, music therapy and massage therapy and also weekly visits from PT, OT and speech.
Fiona had tube feedings 2 hours on, 2 hours off and then continuously throughout the night. She had 9 different medications multiple times a day and she needed to be suctioned when necessary.
We continued to live our lives as normal as we possibly could while caring for Fiona 24/7 and raising Karter and Maggie. Shortly after Fiona was diagnosed, we found the NKH International Family Network online and it was incredibly helpful to be able to connect with other families whose kids also had NKH. It is here where we found support, encouragement and advice on how to deal with various issues. We attended an NKH Conference in Ohio in 2007 and we met Dr. Van Hove for the first time along with some of the families that we had been in contact with.
Fiona was a fighter in every sense of the word and she fought with everything she had. However, she lost her fight with NKH on February 17, 2009 just 2 months shy of her 3rd birthday.
Our connection to Notre Dame is by way of Mary's Dad and brother, who are both ND graduates. Walter Nohelty graduated in 1957 and Sean Nohelty in 1997.We knew Joe and Michelle Sarb only from the NKH Family Network via Facebook and learned about their son, Owen who also had NKH. One day, Joe had posted that there was a very good possibility that Notre Dame would be researching NKH. It is then that we learned about the Sarb Family history with Notre Dame and we got in touch with Joe's parents, Pat and Lynda Sarb.
From there, we found that Pat and Lynda had been in discussion with Notre Dame for awhile about starting NKH research. In Early October 2015, the Sarb's went out to Colorado to meet with Dr. Van Hove and personally invite him to Notre Dame to meet Dr. Kasturi Haldar and the staff at the CRNO. A few weeks later, John, Mary, and Sean (Mary's brother) made the trip down to Notre Dame to meet Pat and Lynda Sarb, Dr. Kasturl Haldar, Dr. Suhail Alam and Barb Calhoun to learn more about the research that had recently been started.
It was very encouraging to hear about the plans and it was personally fulfilling to hear about the deep personal and professional commitment that Dr's Haldar, Alam and others at the CRND have.
We attended our first WORLD RARE DISEASE DAY at Notre Dame in February of 2016. Dr. Van Hove was one of the key speakers along with other doctors, ND students, and families whose lives have been affected by rare diseases.
Dr. Kasturi Haldar, Pat Sarb and Mary were asked to be a part of ND DAY in April 2016. The interview can be seen at https://www.youtube.com/watch?v+n8X-NiTQy0&t=2s $6,000 was raised in about 30 hours, plus a $5,500 share of the matching challenge.
Our son Karter decided to design a wristband in memory of his little sister, Fiona. It went over very well and all of the profits were donated to the "Fighting for Fiona and Friends Fund". We now have designed another wristband to raise awareness of NKH and about the research being done at ND CRND and students of the Rare ND club will be helping us sell them.
Our families created the FIGHTING for FIONA & FRIENDS FUND at Notre Dame in memory of Fiona, as we wanted to be able to pay it forward to those families that have come after us and whose lives have been dramatically impacted by NKH or any other rare disease. 100% of the donations go towards NKH research at the ND CRND.
We are very excited about the progress that Notre Dame has made in just a little over a year and hope that with the continued efforts or all donors, progress can be made to help patients with NKH and numerous other rare diseases.
Mary & John Fitzpatrick
By Pat Sarb 76, '78 Notre Dame Club of Greater DuPage
My family has deep ties to the University of Notre Dame. My great-great grandfather, Louis (Etier) Hickey, a French-Canadian carpenter, was a close friend of Fr. Sorin, and helped build, and rebuild some of the earliest buildings on campus. I was fortunate to have been awarded a football scholarship by Ara Parseghian, and played on Notre Dame's 1973 National Championship team. When my Mom was born, her next door neighbor was Knute Rockne, and my grandfather, Thomas Hickey, Sr., was Rockne's Godfather when he became Catholic in 1925. My Uncle Lou Hickey played for Elmer Layden in the 1930's and our son Matt played for Bob Davie from 1998-2001. In what would have been my last chance to "suit up" for my final home game in 1975, I gave up my spot, without regrets, so Dan “Rudy” Ruettiger could dress. Now my family is "playing" for another great Notre Dame team, the Boler Parseghian Center for Rare and Neglected Diseases!
In the mid·1990's the Notre Damo family started hearing reports of the Parseghian family's now well- known fight against, and battle to find a cure for,Niemann-Pick Type C (NPC) disease. My wife Lynda and I donated what we could to the Ara Parseghian Medical Research Foundation (APMRF), and to former Science Dean Greg Crawford's Road to Discovery bike rides across the U.S. for rare disease research.
Then, on September 22, 2011 my family’s experience with rare diseases became deeply personal when our grandson Owen was born with a rare genetic disease called glycine encephalopathy, or nonketotic hyperglycinemia (NKH). NKH is caused by the shortage, or mutation of an enzyme that normally breaks down glycine in the body. A lack of this enzyme allows excess glycine to build up in tissues and organs, particularly the brain and muscle tissue, leading to serious medical problems.
It was several weeks before our son Joe and his wife Michelle were told by a pediatric geneticist and foremost NKH researcher from UC Denver Children's Hospital, Dr. Johan van Hove, that Owen had NKH. Joe and Michelle later learned that Owen was the only known case in the state of Iowa.
We were at a loss as to what to do next, but I knew exactly where to turn. I contacted Cindy Parseghian (ND '77), president of the APMRF, for suggestions. Cindy wisely told me contact Dr. Kasturi Haldar, the Nieuwland Professor in the Department of Biological Sciences and the Parson-Quinn Director of the Parseghian Center for Rare and Neglected Diseases in the College of Science. In Cindy's recommendation to contact Dr. Haldar, she said, "Kasturi Haldar is a tremendous lady and accomplished researcher.” Cindy couldn’t have been more right with her referral!
Lynda and I first met with Dr. Haldar, Dean Crawford, and the staff of the Boler-Parseghian Center for Rare and Neglected Diseases (CRND) in September 20, 2013. We were on campus that weekend for the 40th reunion of the 1973 championship team with Ara and most of the team.
Dean Crawford, Dr. Haldar, and the entire CRND team were very receptive and open to NKH research possibilities. They made us feel like an important part of the team from the first day. Discussions followed later that fall between Dr. Haldar and Dr. Van Hove. As CRND staff were developing their NKH research strategy, Joe and Michelle traveled with Owen from Davenport, IA to Notre Dame In July 2014, and met with Dean Crawford and the CRND staff.
Another amazing characteristic of CRND that has truly impressed me is that the research teams want to meet with the families and the "patients.' This personalizes their research and gives them greater Incentive to find a cure.
Of course fundraising is a major part of academic research. In December 2014, with an initial donation from Lynda and me, the Development Office set up a CRND fund dedicated 100% to NKH research. From that point it was full steam ahead.
Dean Crawford certainly knew how to raise funds with his Road to Discovery bike rides across America. On his final cross-country ride in June 2015, Greg "rested" in Davenport, Iowa, the hometown of Joe, Michelle and Owen. He attended the Universal Notre Dame Celebration and fundraiser put on by a great team of volunteers from the ND Club of the Quad Cities, led by Club President, Tony Scott '83. Prior to the dinner, 1947 Heisman Trophy winner Johnny Lujack "48 (and my Dad's classmate) made a surprise appearance and gave a generous donation to NKH.
Dr. Van Hove is the leading NKH researcher and medical expert. I felt that we had to get the CRND and Dr. Van Hove working together to find a cure. In my initial email to Dr, Haldar in September 2013. I wrote: "There may be a significant research benefit if I can conned the two medical research teams. My hope and prayer is that combining the knowledge and research of your teams will speed up the cure for both NPC and NKH." In my initial communications with Dr. Van Hove he was a little skeptical about working with a research team from another university. I told him that Notre Dame is different, using NPC research as an example of cooperative efforts with other research Institutes.
In October 2015, Lynda and I flew to Denver and arranged to have a “meet and greet” dinner with Dr. Johan Van Hove. During that dinner, we personally invited him Notre Dame on behalf of CRND's Director, Dr. Kasturi Haldar, to visit the research team at Notre Dame. Dr. Van Hove graciously accepted the invitation and visited campus for the first time on November 13th, 2015 where he met with the CRND research staff, faculty, fellows, students, and Science Dean Mary Galvin.
Dr. Van Hove and CRND are the only entities currently researching NKH in the United States. A giant collaborative leap took place between the two research teams that crisp November day on campus last fall. Together, the goals and landmarks for NKH therapies are within reach. As Dr. Haldar stated in an email to Lynda and me shortly after her initial meeting with Dr. Van Hove, “it marks a very hopeful start on rapidly testing a new therapy for NKH."
Similar to NPC, NKH is inherited in an autosomal recessive manner, which also means either my wife Lynda, or I also carry the genetic mutation. Unlike NPC (chromosome 18), NKH has been traced to mutations in chromosome 3, 9, and 16 Most affected individuals have a defect in the P-protein (Chromosome 9p22).
NKH currently has no treatment or cure. There are only a few hundred cases of NKH in the U.S. The most common form of NKH, which our grandson Owen has, presents itself shortly after birth. Affected infants experience a progressive lack of energy (lethargy), feeding difficulties, and weak muscle tone (hypotonia), abnormal jerking movements, and life-threatening problems with breathing. Most children who survive these early signs and symptoms develop profound intellectual disability and seizures that are difficult to treat.
On February 25, 2016 Notre Dame's College of Science released an article "New formulation or FDA-approved drug may help treat Niemann-Pick Type C disease." Dr, Haldar, Dr. Alam and Ms. Getz from CRND developed and tested a new triple combination formulation (TCF) that delivers the FDA-approved HDACI prescription medication Vorinostat across the blood brain barrier and into brain tissue of mice in a regimen that is safe, improves brain function, disease and animal survival. They also have results suggesting it may help another rare neurological diseases like NKH. A new company has been formed by "Golden Domers” William Claypool '72 and Dennis Wilson '73 to develop the Notre Dame formulation into a drug to treat patients.
What is so exciting for my family, and all families who have been impacted by NKH, is that Notre Dame's NPC research team, with the support of UC Denver’s Dr. Johan Van Hove, is now working on similar strategies for NKH therapies. They are also jointly working on finding new drugs tailored for NKH from the drug compound library of Eli Lilly and Company, with whom CRND has established a partnership.
Since December 2014 we have helped raise over $70,000 for CRNO's NKH research, but we have a long way to go! CRND needs a minimum of $75,000 annually to help pay for a dedicated NKH researcher. Another $40,000 is needed to develop new mouse models to accelerate the path of new drug discovery for NKH. CRND recently announced that the Fitzpatrick and Nohelty families (Mary & John Fitzpatrick and Mary's brother Sean Nohelty '97) made a 5-year commitment of $100,000 to NKH research over the next five years. The fund is called "Fighting for Fiona and Friends" in memory of John and Mary's daughter Fiona, who lost her battle with NKH.
One hundred percent (100%) of all donations to Notre Dame's NKH fund go directly toward NKH research.
Kasturi Haldar, Mary Fitzpatrick and I were also asked to take part in the April 2016 ND Day during "prime time’ on April 25th.
With the help of my Golden Domer classmates, family and friends we raised around $6,000 in less than 30 hours, plus a $5,500 share of the challenge match. We finished an impressive 40th out of some 850 campus ND organizations!
Go Irish. Beat NKH!!!