title: Creatine transporter deficiency: Novel mutations and functional studies.
abstract: X-linked cerebral creatine deficiency (MIM 300036) is caused by deficiency of the creatine transporter encoded by the SLC6A8 gene. Here we report three patients with this condition from Israel. These unrelated patients were evaluated for global developmental delays and language apraxia. Borderline microcephaly was noted in one of them. Diagnosis was prompted by brain magnetic resonance imaging and spectroscopy which revealed normal white matter distribution, but absence of the creatine peak in all three patients. Biochemical testing indicated normal plasma levels of creatine and guanidinoacetate, but an increased urine creatine/creatinine ratio. The diagnosis was confirmed by demonstrating absent ([14])C-creatine transport in fibroblasts. Molecular studies indicated that the first patient is hemizygous for a single nucleotide change substituting a single amino acid (c.619 C > T, p.R207W). Expression studies in HeLa cells confirmed the causative role of the R207W substitution. The second patient had a three base pair deletion in the SLC6A8 gene (c.1222_1224delTTC, p.F408del) as well as a single base change (c.1254 + 1G > A) at a splicing site in the intron-exon junction of exon 8, the latter occurring de novo. The third patient, had a three base pair deletion (c.1006_1008delAAC, p.N336del) previously reported in other patients with creatine transporter deficiency. These three patients are the first reported cases of creatine transporter deficiency in Israel.
authors.affiliation: Research and Development, ARUP Laboratories, Salt Lake City, UT, USA; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA; Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: O
authors.initials: O
authors.lastname: Ardon
authors.affiliation: Research and Development, ARUP Laboratories, Salt Lake City, UT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Procter
authors.affiliation: Research and Development, ARUP Laboratories, Salt Lake City, UT, USA; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA; Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mao
authors.affiliation: Research and Development, ARUP Laboratories, Salt Lake City, UT, USA; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA; Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: N
authors.initials: N
authors.lastname: Longo
authors.affiliation: Edmond and Lily Safra Children's hospital and Sackler Faculty of Medicine, TAU, Sheba Medical Center, Israel.
authors.forename: Y E
authors.initials: YE
authors.lastname: Landau
authors.affiliation: Edmond and Lily Safra Children's hospital and Sackler Faculty of Medicine, TAU, Sheba Medical Center, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Shilon-Hadass
authors.affiliation: Edmond and Lily Safra Children's hospital and Sackler Faculty of Medicine, TAU, Sheba Medical Center, Israel.
authors.forename: L V
authors.initials: LV
authors.lastname: Gabis
authors.affiliation: Edmond and Lily Safra Children's hospital and Sackler Faculty of Medicine, TAU, Sheba Medical Center, Israel.
authors.forename: C
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: Edmond and Lily Safra Children's hospital and Sackler Faculty of Medicine, TAU, Sheba Medical Center, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Tzadok
authors.affiliation: Edmond and Lily Safra Children's hospital and Sackler Faculty of Medicine, TAU, Sheba Medical Center, Israel; Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital and The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Heimer
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA; Edmond and Lily Safra Children's hospital and Sackler Faculty of Medicine, TAU, Sheba Medical Center, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Sada
authors.affiliation: Edmond and Lily Safra Children's hospital and Sackler Faculty of Medicine, TAU, Sheba Medical Center, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Ben-Zeev
authors.affiliation: Edmond and Lily Safra Children's hospital and Sackler Faculty of Medicine, TAU, Sheba Medical Center, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Anikster
keywords: Creatine deficiency; Creatine transport; Creatine transporter deficiency; HELA cells; Human fibroblasts; SLC6A8