The second family with AGAT deficiency (creatine biosynthesis defect): diagnosis, treatment and the first prenatal diagnosis. K. Johnston1, L. Plawner1, L. Cooper1, G.S. Salomons2, N.M. Verhoeven2, C. Jakobs2, A.J. Barkovich3. 1) Kaiser Permanente, San Francisco, CA; 2) VU University Medical Center, Amsterdam, The Netherlands; 3) Department of Radiology, University of California, San Francisco, CA.
Deficiency of arginine:glycine amidinotransferase (AGAT), the first step in creatine biosynthesis, has been described in three related individuals. We describe a new unrelated 3-year-old girl. She showed delayed motor milestones from 4 months of age. At 14 months she had moderate hypotonia, developmental delay and failure to thrive. After demonstrating moderate generalized organic aciduria, she was found to have extremely low levels of guanidinoacetic acid in urine (<0.3 mmol/mol creatinine) and plasma (<0.05 uM/l), with low plasma creatine (2.3 uM/l). Single voxel proton magnetic resonance spectroscopy (MRS) of the brain showed absence of creatine. AGAT activity was not detectable in lymphoblasts. DNA sequence analysis of the AGAT gene revealed a homozygous mutation (IVS3+1G>T), which results in the skipping of exon 3 (r.289_484del196). The parents are carriers of this mutation. In a subsequent pregnancy of the family, DNA isolated from CVS was found to be homozygous for the IVS3+1G>T mutation. At age 16 months, Bayley Infant Development Scale (BIDS) showed functioning at 7 month level (43% of chronologic age). Oral creatine supplementation (400 mg/kg/d) was begun. Growth rate accelerated to the normal range. BIDS at 18 months showed developmental age of 10 months, a clear increase in developmental trajectory. Creatine dose was increased to 600 mg/kg/d at 20 months, and reduced to 400 mg/kg/d at 27 months. BIDS at 29 months showed Mental Scale at 23 months and Motor Scale at 25 months (80% and 86% of chronologic age). Partial recovery of cerebral creatine levels was demonstrated on MRS at 25 months of age. Brain MRS at 33 months of age revealed creatine/NAA ratio about 50-60% of normal, compared with age-matched contols. Presenting symptoms of AGAT deficiency (developmental delay and hypotonia) are non-specific. Early identification and treatment of AGAT deficiency may lead to improvement of developmental outcome.