Conclusion: Molecular analysis should be pursued on patients with suspicion of creatine deficiency. Since these diseases are treatable, early diagnosis assures early treatment, proper genetic counseling and patient management. Furthermore, identification of mutations aids in carrier and prenatal diagnosis. Background: X-linked creatine transporter (SLC6A8) deficiency presents with developmental delay, seizures and behavioral disturbance in boys due to cerebral creatine deficiency. Oral creatine supplementation generally has not resulted in an improvement in neurological symptoms. Case reports: The first boy presented at age 12 years with autism, developmental delay and seizures. A hemizygous c.1222_1224del TTC (p.408del) mutation was detected. The second boy presented at age 3 with mild global developmental delay with significant speech impairment. A novel hemizygous c.238 T>C (p.Y80H) variant was found in the SLC6A8 gene. MRS for both boys revealed a significantly decreased but not absent creatine peak. In view of the small residual creatine peak on MRS, treatment with oral creatine monohydrate supplementation was initiated. Results: Both boys demonstrated an improvement in developmental abilities, particularly speech, on creatine supplementation. In addition, the first boy became seizure-free and had a resolution of abnormal involuntary movements. Despite a clinical response to creatine supplementation in both boys, the size of the MRS peak remained unchanged on serial MRS studies. Conclusion: Boys with X-linked creatine transporter deficiency with a residual creatine peak on MRS may benefit from supplementation with oral creatine monohydrate. Creatine deficiency syndromes, due to defects in AGAT and GAMT (creatine synthesis pathway) or in SLC6A8 (creatine transporter) are inborn errors of metabolism essentially affecting the brain. Autosomal recessive AGAT deficiency is the least common of the three creatine deficiencies, having been described in only 3 families worldwide. In these patients, AGAT deficiency may be due to nonsense-mediated decay of mRNA due to stop codon mutations. Symptoms include speech delay, mental retardation, epileptic seizures, autism and brain atrophy.