[Cerebral creatine deficiency: first Spanish patients harbouring mutations in GAMT gene]. / Deficiencia cerebral de creatina: primeros pacientes españoles con mutaciones en el gen GAMT.

BACKGROUND AND OBJECTIVE: Brain creatine (Cr) deficiencies are a group of inborn errors of metabolism that are characterized by an absence or severe reduction of brain Cr. Clinically, these patients can display psychomotor/mental retardation and language disorders, commonly associated with epilepsy or movement disorders. Three metabolic defects are known: two affect synthesis - guanidinoacetate metiltransferase (GAMT) and glycine amidinotransferase (AGAT) deficiencies- and one affect the Cr transporter (CRTR). We present the first three Spanish patients with GAMT deficiency, and we compare their clinical phenotype and treatment response with other published cases. PATIENTS AND METHOD: The three patients presented mental retardation, epilepsy and autistic behaviour. Patient 1 also had severe chorea. Diagnosis was done by biochemical and genetic procedures (guanidinoacetate quantification, determination of GAMT activity and mutation analysis in the GAMT gene). RESULTS: An increase of guanidinoacetate was detected in urine and plasma. Brain magnetic resonance spectroscopy revealed low Cr levels. Enzymatic studies revealed a decreased GAMT activity in fibroblasts. Molecular analysis detected pathogenic mutations in the GAMT gene. After the deficiency was confirmed, the patients started treatment with Cr. In addition, patient 2 and 3 received an arginine-restricted diet and ornithine supplements. All them showed a partial improvement. CONCLUSIONS: Patients with GAMT deficiency have an unspecific but relatively constant clinical presentation. Brain Cr deficiency should be considered in patients with mental retardation of unknown aetiology, specially in those with movement disorders or epilepsy. Early diagnosis is important in cases with known treatment such as GAMT deficiency.

Deficiencia cerebral de creatina: primeros pacientes españoles con mutaciones en el gen GAMT / Cerebral creatine deficiency: First Spanish patients harbouring mutations in GAMT gene

Fundamento y objetivo: Los síndromes de deficiencia cerebral de creatina (Cr) constituyen un grupo de enfermedades neurometabólicas caracterizadas por deficiencia o ausencia de Cr en el cerebro. Cursan con retraso del desarrollo/mental y trastornos del lenguaje, y puede asociarse a epilepsia o a trastornos del movimiento. Se conocen 3 defectos: 2 de la síntesis —deficiencia de guanidinoacetato metiltransferasa (GAMT) y argininaglicina amidinotransferasa (AGAT)— y uno del transporte (CRTR). En este trabajo presentamos los 3 primeros pacientes españoles con deficiencia de GAMT y comparamos su fenotipo clínico y respuesta al tratamiento con otros casos publicados. Pacientes y método: Los pacientes presentan retraso mental, epilepsia y conducta autista. La paciente 1 asocia corea grave. Pacientes y método: El diagnóstico se realizó mediante estudios bioquímicos para cuantificar metabolitos específicos y actividad enzimática y genéticos del gen GAMT. Resultados: En orina y plasma se detectó aumento de guanidinoacetato. La resonancia magnética con espectroscopia reveló reducción marcada de Cr cerebral. Los estudios enzimáticos mostraron disminución de la actividad GAMT en fibroblastos y el estudio molecular reveló mutaciones en el gen GAMT. Tras el diagnóstico, se inició tratamiento con suplemento de Cr, y se asoció en los pacientes 2 y 3 una dieta restringida en arginina y suplemento de ornitina, con mejoría parcial. Conclusiones: Los pacientes con deficiencia de GAMT presentan un fenotipo inespecífico pero relativamente constante. Deben buscarse los síndromes de deficiencia cerebral de Cr en pacientes con retraso mental/psicomotor de etiología desconocida, especialmente si se acompañan de trastornos del movimiento y epilepsia. Es importante el diagnóstico precoz en casos tratables como la deficiencia de GAMT (AU)

Background and objetive: Brain creatine (Cr) deficiencies are a group of inborn errors of metabolism that are characterized by an absence or severe reduction of brain Cr. Clinically, these patients can display psychomotor/mental retardation and language disorders, commonly associated with epilepsy or movement disorders. Three metabolic defects are known: two affect synthesis – guanidinoacetate metiltransferase (GAMT) and glycine amidinotransferase (AGAT) deficiencies– and one affect the Cr transporter (CRTR). We present the first three Spanish patients with GAMT deficiency, and we compare their clinical phenotype and treatment response with other published cases. Patients and method: The three patients presented mental retardation, epilepsy and autistic behaviour. Patient 1 also had severe chorea. Diagnosis was done by biochemical and genetic procedures (guanidinoacetate quantification, determination of GAMT activity and mutation analysis in the GAMT gene).Results: An increase of guanidinoacetate was detected in urine and plasma. Brain magnetic resonance spectroscopy revealed low Cr levels. Enzymatic studies revealed a decreased GAMT activity in fibroblasts. Molecular analysis detected pathogenic mutations in the GAMT gene. Results: After the deficiency was confirmed, the patients started treatment with Cr. In addition, patient 2 and 3 received an arginine-restricted diet and ornithine supplements. All them showed a partial improvement. Conclusions: Patients with GAMT deficiency have an unspecific but relatively constant clinical presentation. Brain Cr deficiency should be considered in patients with mental retardation of unknown aetiology, specially in those with movement disorders or epilepsy. Early diagnosis is important in cases with known treatment such as GAMT deficiency (AU)