Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency
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RESEARCH
Open Access
Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency Roberta Battini1*, M. Grazia Alessandrì1, Claudia Casalini1, Manuela Casarano1, Michela Tosetti2 and Giovanni Cioni1,3
Abstract Background: Arginine:glycine amidinotransferase deficiency (AGAT-d) is a very rare inborn error of creatine synthesis mainly characterized by absence of brain Creatine (Cr) peak, intellectual disability, severe language impairment and behavioural disorder and susceptible to supplementary Cr treatment per os. Serial examinations by magnetic resonance spectroscopy are required to evaluate Cr recovery in brain during treatment of high doses of Cr per os, which have been proved beneficial and effective in treating main clinical symptoms. A long term study with detailed reports on clinical, neurochemical and neuropsychological outcomes of the first Italian patients affected by AGAT-d here reported can represent a landmark in management of this disorder thus enhancing medical knowledge and clinical practice. Results: We have evaluated the long term effects of Cr supplementation management in four Italian patients affected by AGAT-d, correlating specific treatments with serial clinical, biochemical and magnetic resonance spectroscopy examinations as well as the neuropsychological outcome by standardized developmental scales. Consecutive MRS examinations have confirmed that Cr depletion in AGAT-d patients is reversible under Cr supplementation. Cr treatment is considered safe and well tolerated but side effects, including weight gain and kidney stones, have been reported. Conclusions: Early treatment prevents adverse developmental outcome, while patients diagnosed and treated at an older age showed partial but significant cognitive recovery with clear improvements in adaptive functioning. Keywords: Creatine synthesis defect, Magnetic resonance spectroscopy, Creatine supplementation, Longterm outcome, AGAT deficiency
Background Arginine:glycine amidinotransferase (AGAT, OMIM 602360) deficiency (AGAT-d) is a very rare inborn error of creatine (Cr) synthesis described in 2000 in an Italian family and successively confirmed by molecular and enzymatic analysis [1, 2]. This disorder is caused by a deficiency of the first enzyme involved in Cr synthesis (Fig. 1), resulting in a commonly recognized biochemical pattern represented by low Guanidinoacetic acid (GAA) concentrations in plasma and urine and low/undetectable * Correspondence: [email protected] 1 Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Viale del Tirreno 331, Calambrone, 56128 Pisa, Italy Full list of author information is available at the end of the article
brain Cr detectable by magnetic resonance spectroscopy (MRS). Main clinical symptoms of this disorder are intellectual disability, severe language impairment and behavioural problems. Similar to guanidinoacetate-methyltransferase deficiency (GAMT-d), another Cr synthesis defect, it is susceptible of supplementation therapy with hig
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