Evaluation of two year treatment outcome and limited impact of arginine restriction in a patient with GAMT Deficiency

Abstract: A 4-year-old female with history of developmental regression and autistic features was diagnosed with guanidinoacetate methyltransferase deficiency at age 21 months. Upon treatment, she showed improvements in her developmental milestones, sensorial-neural hearing loss and brain atrophy on cranial-MRI. The creatine/choline ratio increased 82% in basal ganglia and 88% in white matter on cranial MR-spectroscopy. The CSF guanidinoacetate decreased 80% after six months of ornithine and creatine supplementation and an additional 8% after 18 months of additional arginine restricted diet. We report the most favorable clinical and biochemical outcome on treatment in our patient.

Parent Summary: This case report describes the treatment outcome of a four-year-old girl with GAMT deficiency over the course of two years, treated with creatine and ornithine supplementation and an arginine-restricted diet. She was diagnosed at 21 months, after developmental delays, mild to moderate hearing loss, and measurement of elevated guanidino acetate (GAA) in the urine. The diagnosis was confirmed by DNA sequencing. The patient was monitored for the next two years, measuring GAA in the blood, urine, and cerebrospinal fluid (fluid in the brain and spinal cord), as well as evaluating her hearing and development. Her treatment consisted of creatine and ornithine supplementation (both 400 mg/kg/day), and after 6 months an arginine-restricted diet was introduced (daily limit of 20 mg/kg/day, gradually decreased to 14 mg/kg/day within 14 months). The goal of the arginine restriction was to lower the amount of GAA measured, by blocking the AGAT enzyme from making GAA. Essential amino acid supplement was given to meet protein dietary requirements for her age. After two years of therapy, she was making constant but slow progress in development and her hearing was normal. However, she was still not meeting age appropriate developmental milestones. The amount of GAA measured after two years of therapy remained high in the blood and cerebrospinal fluid, though urinary GAA was within normal range. The authors noted that this was surprising, given the significant arginine restriction to her diet. They suggested that severe arginine restriction may not offer major benefits to GAMT deficiency patients with mild to moderate symptoms, especially given how challenging it is to determine the arginine content of foods (a protein restriction will not necessarily limit arginine appropriately).

Link to article: https://www.sciencedirect.com/science/article/abs/pii/S1096719211003489?via%3Dihub

PubMed:  https://pubmed.ncbi.nlm.nih.gov/22019491/

Authors: Saadet Mercimek-Mahmutoglu, Mary Dunbar, Andrea Friesen, Susan Garret, Carol Hartnett, Linda Huh, Graham Sincalir, Sylvia Stockler, Stephen Wellington, Petra J.W. Pouwels, Gajja S. Salomons, Cornelis Jakobs

Key Terms:  GAMT, Clinical Study, MRS, Diagnostic, Supplements, Pediatric Patient, Female Patient