Emory geneticists Hong Li and Michael Gambello recently identified the first pediatric case of a rare inherited metabolic disorder: glucagon receptor deficiency. Their findings, published in Molecular Genetics and Metabolic Reports, show the power of gene sequencing to solve puzzles – when combined with human intelligence. Although the diagnosis did not resolve all the issues faced by the patient, it allowed doctors to advise the family about diet and possible pancreatic tumor risk.

The family of a now 9-year-old girl came to Li when the girl was 4 years old. Based on newborn screening, the girl had been diagnosed with a known disorder called arginase deficiency. Arginase breaks down the amino acid arginine; if it is deficient, arginine and toxic ammonia tend to accumulate. At birth, the girl had high arginine levels – hence the initial diagnosis.

The girl had a history of low body weight, anorexia and intermittent vomiting, which led doctors to place a feeding tube through the abdominal wall into her stomach. For several years, she was given a special low-protein liquid diet and supplements, aimed at heading off nutritional imbalance and tissue breakdown. However, she did not have intellectual disability or neurological symptoms, which are often seen with arginase deficiency.

In fact, her blood amino acids, including arginine, were fully normalized, and a genetic test for arginase deficiency was normal as well. These results were perplexing. By reviewing all the clinical, biochemical and molecular data, Li concluded the girl did not have arginase deficiency, and began looking for an alternative diagnosis.

Li advised that the family could try to slowly transition the girl to a more conventional diet. Unfortunately, the elevated amino acid levels, which had been kept away by the special diet, came back. “We monitored her very closely,” Li says, adding that she wanted to avoid exposing the girl to neurotoxic levels of amino acids, such as glutamine and arginine.

Li and Gambello had also performed exome sequencing to look for other mutations that may be causing her metabolic problems. Initially, this didn’t identify anything. Li searched biomedical literature under “hyperaminoacidemia” and ran across a paper about mice lacking the gene for the glucagon receptor. The profiles were exactly the same, down to which amino acids were elevated. They took another look at the girl’s exome sequencing data for the gene of glucagon receptor (GCGR) – and the girl had a mutation there, which had not been annotated in genomic databases.

Glucagon, a hormone formed in the pancreas, promotes the breakdown of glycogen into glucose. We can think of it as the opposite of insulin – insulin makes cells suck up glucose, while glucagon will throw more glucose into the system. Li says the connection between glucagon signals in the liver and amino acids is not well known, and it’s not surprising that others missed it, since it involves a crossover between endocrinology and biochemical genetics.

Adults with deficiency in the glucagon receptor have been previously identified, Li says. They usually come to the attention of doctors because of an enlarged pancreas or neuroendocrine tumors, a phenomenon called Mahvash disease. In animal studies, it appears that the high levels of amino acids, especially glutamine, may cause overgrowth by pancreatic alpha cells, leading to the tumors. However, the girl’s case is different –gastrointestinal symptoms have not been previously seen in adults. This may be explained by the particular mutation in the glucagon receptor she has. Right now, Li doesn’t know whether the girl faces higher risk of pancreatic tumors.

Hong Li, MD, PhD

For the girl’s family, the genetic diagnosis is a mixed blessing. They can perform surveillance for pancreatic tumors, and monitor her diet, although strict protein restriction may become more difficult as she gets older. Li says definitive guidance for dietary management in preventing pancreas tumors in human is lacking. Right now, the girl continues to be fed through the feeding tube, with supplements at night, for nutritional support.

Li is thankful for the continued cooperation with the girl’s family. “Without that collaboration and trust, we wouldn’t get an answer,” she says.

After this case, Li says that recognizing the unique pattern of amino acids may help identification of other gene mutations involved glucagon signaling. Other genetics lab directors have told her they’ve seen similar confounding cases. Li and Gambello are currently working on creating a mouse model of their patient’s genetic defect to better understand the pathways leading to poor weight gain. In addition, they are investigating whether other genetic defects can disrupt glucagon signaling and cause disease. They may find others — today it is possible for families of children with rare genetic disorders to organize themselves rapidly. The NGLY1 story, which Gambello was part of, is one example.