title: Mild guanidinoacetate increase under partial guanidinoacetate methyltransferase deficiency strongly affects brain cell development.
abstract: Among cerebral creatine deficiency syndromes, guanidinoacetate methyltransferase (GAMT) deficiency can present the most severe symptoms, and is characterized by neurocognitive dysfunction due to creatine deficiency and accumulation of guanidinoacetate in the brain. So far, every patient was found with negligible GAMT activity. However, GAMT deficiency is thought under-diagnosed, in particular due to unforeseen mutations allowing sufficient residual activity avoiding creatine deficiency, but enough guanidinoacetate accumulation to be toxic. With poorly known GAA-specific neuropathological mechanisms, we developed an RNAi-induced partial GAMT deficiency in organotypic rat brain cell cultures. As expected, the 85% decrease of GAMT protein was insufficient to cause creatine deficiency, but generated guanidinoacetate accumulation causing axonal hypersprouting and decrease in natural apoptosis, followed by induction of non-apoptotic cell death. Specific guanidinoacetate-induced effects were completely prevented by creatine co-treatment. We show that guanidinoacetate accumulation without creatine deficiency is sufficient to affect CNS development, and suggest that additional partial GAMT deficiencies, which may not show the classical brain creatine deficiency, may be discovered through guanidinoacetate measurement.
authors.affiliation: Neurometabolic Unit, Service of Biomedicine, Lausanne University Hospital, CH-1011 Lausanne, Switzerland.
authors.forename: Layane
authors.initials: L
authors.lastname: Hanna-El-Daher
authors.affiliation: Neurometabolic Unit, Service of Biomedicine, Lausanne University Hospital, CH-1011 Lausanne, Switzerland.
authors.forename: Elidie
authors.initials: E
authors.lastname: Béard
authors.affiliation: Neurometabolic Unit, Service of Biomedicine, Lausanne University Hospital, CH-1011 Lausanne, Switzerland.
authors.forename: Hugues
authors.initials: H
authors.lastname: Henry
authors.affiliation: Department of Clinical Neuroscience, Lausanne University Hospital, CH-1011 Lausanne, Switzerland.
authors.forename: Liliane
authors.initials: L
authors.lastname: Tenenbaum
authors.affiliation: Neurometabolic Unit, Service of Biomedicine, Lausanne University Hospital, CH-1011 Lausanne, Switzerland. Electronic address: Olivier.Braissant@chuv.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Braissant
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001369:Axons / Q000201:enzymology; D001921:Brain / Q000196:embryology* / Q000201:enzymology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003401:Creatine / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D005822:Genetic Vectors; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism; D050937:Guanidinoacetate N-Methyltransferase / Q000172:deficiency* / Q000235:genetics; D009457:Neuroglia / Q000201:enzymology; D009474:Neurons / Q000201:enzymology; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; D050937:Guanidinoacetate N-Methyltransferase; C004946:glycocyamine; D003401:Creatine; D005998:Glycine
keywords: Adeno-associated virus; Brain; Creatine; Creatine deficiency syndromes; Development; GAMT deficiency; Guanidinoacetate; RNA interference