The first pediatric case of glucagon receptor defect...

The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine.

Hong Li, Lihua Zhao, Rani Singh, J. Nina Ham, Doris O. Fadoju, Lora J. H. Bean, Yan Zhang, Yong Xu, H. Eric Xu, Michael J. Gambello

Molecular Genetics and Metabolism Reports 17 (2018) 46-52.


Emory University geneticists report on the first pediatric identification of Mahvash Disease* (Glucagon receptor defect – autosomal recessive, predisposing to pancreatic alpha-cell hyperplasia and pancreatic neuroendocrine tumors), previously described only in adults and whose presentation included a pancreatic mass. The patient was a 7-year old fraternal twin, born of Indian parents who were first cousins once removed. Newborn screening was notable for an elevated arginine level.

Initial management consisted of a low protein diet supplemented with essential amino acid formula, and an ammonia scavenger drug (Na+ phenyl butyrate) for presumptive arginase deficiency. However, follow-up arginase enzyme assay and ARG1 gene sequencing and deletion and duplication analysis were normal, thus original treatment strategies were abandoned but then hyperaminoacidemia recurred, predominantly glutamine, alanine, lysine, arginine, ornithine, threonine, and serine. Clinically, she maintained a lean body habitus, experienced spells of anorexia and emesis, but maintained normal intellectual prowess and an unremarkable neurological exam.  Her growth curve flattened from age four to seven. Despite plasma hyperaminoacidemia, CSF amino acid levels were normal. Further PubMed inquiry utilizing “hyperaminoacidemia” located a similar pattern reported in glucagon knockout mice. A reanalysis of the exome performed at age four, with attention to the GCGR gene, revealed a homozygous c.958_960del (p.Phe320del) variant. Both parents were heterozygous for the variant. The patient’s glucagon level was 27,000 pg/dL (normal < 270). She proved completely unresponsive to exogenous glucagon stimulation after fasting. In vitro functional studies confirmed a mutant GCGR protein that interrupts glucagon signalling. Computer modelling demonstrated rotation of the transmembrane domain 5 (TMD5) helix, resulting in a conformational change which altered G protein binding with subsequent signalling defect.

Her gastrointestinal symptoms remain puzzling, in that adults identified with glucagon receptor deficiency do not report similar symptoms. Compared to total-loss–of-function mutation types in all reported adult cases, this patient carries only a single amino acid deletion and the mutant protein is able to localize to cell membrane, molecular features that may attribute to its uniqueness. The child also had an elevated LDL cholesterol level possibly secondary to disrupted glucagon signaling. This case is the first known published case of Mahvash Disease in a child without a pancreatic mass, as is seen in adults, and represents the value of newborn screening tests, persistent physicians, recognition of abnormal amino acid patterns, and re-examination of exome analysis with a specific target in mind. 

Submitted by Clyde Partin, MD (Emory University), with the permission of Hong Li, MD, PhD & Michael J. Gambello, MD, PhD.

*The index case of Mahvash Disease was reported by Run Yu, NN Nissen and colleagues in Pancreas 36 (4) 2008: 428-431.  Mahvash is derived from the name of the first patient identified with this disease.


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