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Disorders of creatine synthesis or transport
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Treatment with supplemental creatine (CR), a dose of 400 mg/kg per day, was employed and resulted in significant improvement in patients with AGAT and GAMT deficiencies. In three patients with AGAT deficiency, there was rapid improvement in fine-motor skills and in behavior disorder; these improvements paralleled the increase in brain levels of creatine. Speech and cognition remained significantly impaired. In GAMT deficiency, oral supplementation in the first three reported patients, with creatine monohydrate in doses of 0.35–2.0 g/kg per day, resulted in gradual increase in the CNS creatine signal on MRS, but it was still significantly below normal. GAA levels remained high, suggesting the possibility that the compound may inhibit the transport of creatine into the CNS. The index patient did show significant clinical improvement; the movement disorder, swallowing difficulties, and seizure disorder resolved. His gross motor function improved, and he was able to walk at the age of five years. He continued to have some autistic and self-injurious behavior. Another patient showed improved psychomotor function and resolution of the seizures and globus pallidus lesions. A third showed no improvement; seizures continued. In our patients, dietary arginine restriction and ornithine supplementation (100 mg/kg per day) with an arginine-free essential amino acid formula (0.4 g/kg per day), resulted in significant reduction of plasma GAA and improvement in seizure activity and EEG [18, 23]. Current treatment with 400(–800) mg/kg of creatine and ornithine and restriction of arginine intake has led regularly to improvement [8]. Replenishment of the cerebral creatine pool takes months to years and is not complete. Most patients have reached a plateau, but in our patients, therapeutic result has been rewarding. Presymptomatic treatment of neonates has resulted in normal development [24], and we have seen near normal development in patients which were diagnosed and treated since infancy, diagnosed after a first seizure. Early diagnosis and initiation of treatment in the first months of life appears to prevent development of symptoms, as also shown in the brother of two AGAT-deficient sisters, who was diagnosed at birth, treated pre-symptomatically with oral Cr and did not develop the neurologic symptoms of AGAT deficiency [25]. Creatine supplementation therapy should be monitored for the possible development of creatine-associated nephropathy [26]. Inclusion of GAMT deficiency into newborn screening programs has now been developed with measuring GAA in blood spots and GAMT gene sequencing in positive samples [27].
Preclinical and clinical developments in enzyme-loaded red blood cells: an update
Published in Expert Opinion on Drug Delivery, 2023
Marzia Bianchi, Luigia Rossi, Francesca Pierigè, Sara Biagiotti, Alessandro Bregalda, Filippo Tasini, Mauro Magnani
Creatine deficiency disorders (CDDs) are inborn errors of creatine metabolism and transport, which can be caused by three different gene defects: guanidinoacetate methyltransferase (GAMT) deficiency, L-arginine:glycine amidinotransferase (AGAT) deficiency and creatine transporter (CRTR) deficiency [98]. Although they share common traits (developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder), GAMT deficiency can present the most severe phenotype, and is characterized by neurocognitive dysfunction due to creatine (Cr) deficiency and accumulation of guanidinoacetate (GAA) in the brain. GAMT catalyzes the second and final step of creatine biosynthesis (which occurs primarily in the liver, kidneys, and pancreas), through methylation of guanidinoacetate, employing S-adenosylmethionine (SAM) as methyl donor [99]. Although likely under-diagnosed [100], GAMT deficiency is a rare disease with a prevalence of < 1/1,000,000 [101]. Numerous loss-of-function mutations (mainly of missense type) are scattered throughout the gene [102]. GAMT deficiency is characterized, from a biochemical standpoint, by low levels of Cr, which plays an essential role in energy homeostasis, and by the concomitant accumulation in tissues and bodily fluids of its precursor GAA, whose toxicity, mainly for the brain, has been implicated in the pathophysiology of the disorder [99,103,104].
Benefits and drawbacks of guanidinoacetic acid as a possible treatment to replenish cerebral creatine in AGAT deficiency
Published in Nutritional Neuroscience, 2019
GAA (otherwise known as glycocyamine) is further converted to creatine in the second step of the process.2 Hence, AGAT deficiency is characterized by low brain levels of both GAA and creatine, accompanied by mild to moderate intellectual disability, delayed speech development and motor skills, and myopathy.3 Although this disorder has been identified in only a few families,4 severe features of AGAT deficiency require well-targeted treatment protocols to restore brain creatine levels. Traditional management of AGAT deficiency entails long-term oral creatine monohydrate administration (100–800 mg/kg/day) that results in almost complete restoration of brain creatine levels and improvement of clinical characteristics. However, creatine treatment might be somewhat limited due to possible shortcomings in performance and transport of creatine to the brain, at least in some cases of AGAT deficiency.4 Recent studies reported superiority of supplemental GAA vs. creatine to improve brain creatine levels in Yucatan miniature pigs5 and healthy humans,6 suggesting GAA as a possible alternative to creatine to tackle brain creatine levels even in clinical environment. This paper discusses advantages and disadvantages of GAA as a possible treatment to replenish brain creatine levels in AGAT deficiency.