Texas Children's Hospital
Texas Children's Hospital

A Family Donation Funds Research for Rare Neurological Disorder

A Family Donation Funds Research for Rare Neurological Disorder

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A rare and mysterious neurological disorder inspired the Wilsey family of San Francisco to fund researchers at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and the Department of Molecular & Human Genetics at Baylor College of Medicine to study and develop treatments for NGLY1 deficiency. The Wilseys’ daughter, Grace, is one of only 14 known children worldwide affected by the rare condition, which is characterized by a mutation in the gene coding for N-glycanase 1, an enzyme that is thought to help recycle defective products from a cellular assembly line. Children who lack this enzyme experience varying degrees of movement disorders, suffer from developmental delays, have liver and gastrointestinal problems and cry without producing tears.

After a lengthy saga of visiting with physicians across the nation searching for answers about Grace’s condition, the Wilsey family finally found the answer after a meeting with Huda Zoghbi, M.D., Howard Hughes Medical Institute investigator and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. Zoghbi examined Grace and recommended a new test called whole genome sequencing, which helped identify Grace as the second child in the world diagnosed with NGLY1 deficiency. Experts at Texas Children’s Hospital and Baylor used the new test to decode the DNA sequence of her genome allowing them to identify abnormal genes. The technology helps patients and families understand the cause of neurologic diseases, as well as the risk of recurrence.

In Grace’s case, the testing provided researchers eight different genes, including NGLY1, and they began investigating the genes in order of the likelihood that they might explain her disease.

Matthew Bainbridge, Ph.D., post doctoral associate in the Human Genome Sequencing Center at Baylor, ultimately solved the mystery after scouring the medical literature and identifying another child with similar unusual symptoms, which were tied to an NGLY1 gene defect.

“Having the support and engagement of the Wilsey family was critical to solving this case and their ongoing efforts in patient-research advocacy will be paramount to solving more genetic diseases in the future,” said Bainbridge.

The research was published in a recent issue of the journal Genetics in Medicine.

“Whole genome sequencing has been a powerful tool in diagnosing some of the most challenging cases and we are increasingly finding patients with rare syndromes who have been through a battery of previous tests without a diagnosis,” said Richard Gibbs, Ph.D., director of the Human Genome Sequencing Center at Baylor.

Hamed Jafar-Nejad, M.D., in consultation with Zoghbi, is leading research efforts for NGLY1 deficiency at Baylor and the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital. The Baylor/NRI group is using fruit flies to understand the cellular and physiological defects caused by the loss of NGLY1 and to identify potential therapeutic targets for the disease.

These studies are coordinated with those of a group of researchers around the world who are using biochemical, cell biological, mouse genetics and systems biology approaches to understand the biology of NGLY1 and the pathophysiology of NGLY1 deficiency. It is hoped that this multidisciplinary approach, which has been made possible by generous funds from the Wilsey family, will significantly expedite the progress of this project and will lead to the identification of a therapy for NGLY1 deficiency.

— Veronika Javor Romeis, Texas Children’s Hospital 

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