title: [Cerebral creatine deficiency syndromes].
abstract: BACKGROUND
  Creatine deficiency syndromes are a recently described group of diseases characterized by inborn errors of creatine metabolism. Clinical features include a spectrum of neurodevelopment disorders of diverse severity. They are characterized by low levels of cerebral creatine caused by different pathogenic mutations concerning the genes coding for creatine synthesis enzymes [arginine: glicyne amidinotransferase (AGAT, EC 2.1.4.1) and guanidinoacetate methyltansferase (GAMT, EC 2.1.1.2)], AGAT and GAMT, respectively, or its transporter (CT1 deficiency), SLC6A8. Enzymatic deficiencies are transmitted as autosomal recessive traits, whereas the transporter deficit is X-linked.
  
  
  OBJECTIVE
  To characterize the clinical and laboratorial presentation, diagnosis and treatment of cerebral creatine deficiency patients, followed in Hospital Pediátrico Carmona da Mota. The awareness of these inborn errors of metabolism as neurological disorders, namely of neurodevelopment, among the medical community is a secondary aim of the present work.
  
  
  METHODS
  Retrospective analysis of the clinical files of patients followed in our Hospital and diagnosed with cerebral creatine deficiency syndrome.
  
  
  RESULTS
  Twelve patients belonging to seven different families were diagnosed with creatine deficiency syndromes. Five presented GAMT deficiency and seven CT1 deficiency. Present ages are 2 to 38 years old. The most common clinical presentations were: global development delay in seven patients (two with epilepsy), and speech delay in two patients. Only one patient had communication and social interaction dysfunction. In all, global development delay in the range of intellectual delay was identified. The pathognomonic pattern of cerebral creatine deficiency in the brain image was demonstrated in eight patients. Pathogenic mutations in GAMT or SLC6A8 genes were identified in all cases.
  
  
  CONCLUSIONS
  The suspicion of cerebral creatine depletion must be considered in all children presenting unexplained global psychomotor development delay. Pre-symptomatic therapy has shown promising results, especially in GAMT deficiency patients. The high rate of asymptomatic carriers of GAMT mutations in our population makes this disorder eligible to neonatal screening in Portugal.
authors.affiliation: Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Malheiro
authors.forename: Luísa
authors.initials: L
authors.lastname: Diogo
authors.forename: Paula
authors.initials: P
authors.lastname: Garcia
authors.forename: Isabel
authors.initials: I
authors.lastname: Fineza
authors.forename: Guiomar
authors.initials: G
authors.lastname: Oliveira
mesh_terms: D000328:Adult; D020739:Brain Diseases, Metabolic, Inborn / Q000175:diagnosis*; D003401:Creatine / Q000172:deficiency*; D005260:Female; D050937:Guanidinoacetate N-Methyltransferase / Q000172:deficiency*; D006801:Humans; D007805:Language Development Disorders / Q000175:diagnosis*; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency*; D009069:Movement Disorders / Q000151:congenital* / Q000175:diagnosis; D012189:Retrospective Studies; D013577:Syndrome; D055815:Young Adult
chemical_list: D026901:Membrane Transport Proteins; C080679:creatine transporter; D050937:Guanidinoacetate N-Methyltransferase; D003401:Creatine