[Cerebral creatine transporter deficiency: an infradiagnosed neurometabolic disease]. / Deficiencia del transportador de creatina cerebral: una enfermedad neurometabolica infradiagnosticada.

INTRODUCTION: Brain creatine deficiencies are a group of inborn errors of metabolism recently recognized which are caused by arginine: glycine amidinotransferase (AGAT) deficiency, guanidinoacetate metiltransferase (GAMT) deficiency and defects in creatine transporter (CRTR). Although all of them are characterized by a brain creatine deficiency, clinical and biochemical features are different. CASE REPORTS: We present a retrospective study about four patients of masculine sex affected of creatine transporter defects who were recently diagnosed in our centre. We describe the clinical presentation features, the different tests that we used in the diagnosis process (brain magnetic resonance spectroscopy, biochemical analysis of guanidinoacetate and creatine/creatinine ratio in urine), evolution aspects and the response to treatment. The most significative clinical feature was developmental delay mainly in expressive speech, they also presented epilepsy (three cases), autism (three cases), hypotonia (one case) and microcephalia (one case). Brain magnetic resonance spectroscopy showed a low (three cases) or an absence (one case) of creatine level. To confirm the defect we studied the creatine uptake in fibroblasts and molecular analysis of the SLC6A8/creatine transporter gene. Patients with creatine transporter deficiency are being treated with arginine, because a lack of response to creatine. CONCLUSION: Cerebral creatine transporter deficiency can present with different neurological symptoms but developmental and language delay and epilepsy are the most significative; diagnosis is easy and there are some therapeutical options.

Deficiencia del transportador de creatina cerebral: una enfermedad neurometabólica infradiagnosticada / Cerebral creatine transporter deficiency: an infradiagnosed neurometabolic disease

Introducción. Las deficiencias de creatina cerebral constituyen un grupo de errores congénitos del metabolismo que se ha conocido recientemente e incluye las deficiencias de guanidinoacetato metiltransferasa (GAMT), de arginina-glicina amidinotransferasa (AGAT) y del transportador de creatina (CRTR). Aunque todos ellos se caracterizan por un déficit de creatina en el cerebro, las manifestaciones clínicas y bioquímicas son distintas. Casos clínicos. Presentamos un estudio retrospectivo de cuatro pacientes de sexo masculino con defectos del transportador de creatina diagnosticados en nuestro centro recientemente, para analizar la forma de presentación clínica, las pruebas complementarias utilizadas para su diagnóstico (resonancia magnética con espectroscopia), valoración de guanidinoacetato y relación creatina/creatinina en orina), los aspectos evolutivos y la respuesta al tratamiento. El hallazgo más significativo en estos pacientes fue el retraso del desarrollo, principalmente en el lenguaje y el retraso mental. Presentaron, además, epilepsia (tres casos), autismo (tres casos), hipotonía (un caso) y microcefalia (un caso). La resonancia magnética con espectroscopia mostró un descenso (en tres casos) o ausencia (en un caso) del pico de creatina. Se confirmó el defecto mediante un estudio de incorporación de creatina en fibroblastos y estudios moleculares del gen SLC6A8. Los pacientes con defectos del transportador están siendo tratados con arginina, dada la escasa respuesta a la creatina. Conclusión. Los defectos del transportador de creatina pueden presentarse de formas diferentes, pero predominan el retraso del desarrollo y del lenguaje y la epilepsia; su diagnóstico es sencillo y existen opciones terapéuticas

Introduction. Brain creatine deficiencies are a group of inborn errors of metabolism recently recognized which are caused by arginine: glycine amidinotransferase (AGAT) deficiency, guanidinoacetate metiltransferase (GAMT) deficiency and defects in creatine transporter (CRTR). Although all of them are characterized by a brain creatine deficiency, clinical and biochemical features are different. Case reports.We present a retrospective study about four patients of masculine sex affected of creatine transporter defects who were recently diagnosed in our centre. We describe the clinical presentation features, the different tests that we used in the diagnosis process (brain magnetic resonance spectroscopy, biochemical analysis of guanidinoacetate and creatine/creatinine ratio in urine), evolution aspects and the response to treatment. The most significative clinical feature was developmental delay mainly in expressive speech, they also presented epilepsy (three cases), autism (three cases), hypotonia (one case) and microcephalia (one case). Brain magnetic resonance spectroscopy showed a low (three cases) or an absence (one case) of creatine level. To confirm the defect we studied the creatine uptake in fibroblasts and molecular analysis of the SLC6A8/creatine transporter gene. Patients with creatine transporter deficiency are being treated with arginine, because a lack of response to creatine. Conclusion. Cerebral creatine transporter deficiency can present with different neurological symptoms but developmental and language delay and epilepsy are the most significative; diagnosis is easy and there are some therapeutical options

Diagnóstico y tratamiento de los síndromes de deficiencia de creatina cerebral / Diagnosis and treatment of brain creatine deficiency syndromes

Aim. To review the clinical, biochemical and genetic aspects of brain creatine deficiency syndromes, as well as thetherapeutic options available. Development. Brain creatine deficiency syndrome has recently been described as a series ofinborn errors of metabolism that affect the synthesis and transport of creatine. Three metabolic defects are known: two affectsynthesis –guanidinoacetate methyltransferase (GAMT) and arginine:glycine amidinotransferase (AGAT)– and one affectsthe transport of creatine. Clinically, these patients can display mental retardation, language disorders, epilepsy, autisticbehaviour, neurological impairment and movement disorders. After the clinical selection, the different defects can beidentified by a biochemical study involving the analysis of metabolites in biological fluids (guanidinoacetate and creatine/creatinine ratio). Before continuing with the molecular studies, it is important to confirm the deficiency of brain creatine bymeans of magnetic resonance imaging with spectroscopy. Diagnostic confirmation of AGAT and GAMT deficits is carried outby determining the enzymatic activity in fibroblasts or lymphoblasts, or the incorporation of creatine in the case of studiesof transport defects. The study of mutations in AGAT, GAMT (autosomal recessive inheritance) and SLC6A8 (X-linked)genes completes the diagnosis. Conclusions. Brain creatine deficiency syndromes are mainly associated to mental retardationand autism. GAMT and AGAT deficiencies respond to treatment with creatine, whereas patients with transport defects donot respond to this therapy; new therapeutic approaches are therefore being evaluated for this disease

Objetivo. Revisar los aspectos clínicos, bioquímicos ygenéticos, y las opciones terapéuticas en los síndromes de deficienciade creatina cerebral. Desarrollo. Recientemente se ha descrito elsíndrome de deficiencia de creatina cerebral como un conjunto deerrores innatos del metabolismo que afectan a la síntesis y al transportede creatina. Se conocen tres defectos metabólicos: dos afectana la síntesis –deficiencia de guanidinoacetato metiltransferasa(GAMT) y de arginina-glicina amidinotransferasa (AGAT)– y unoal transporte de creatina. Clínicamente, estos pacientes pueden presentarretraso mental, trastornos del lenguaje, epilepsia, comportamientoautista, deterioro neurológico y trastornos del movimiento.Tras la selección clínica, el estudio bioquímico mediante análisis demetabolitos en fluidos biológicos (guanidinoacetato y relación creatina/creatinina) permite identificar los diferentes defectos. Antes decontinuar con los estudios moleculares, es importante confirmar la deficiencia cerebral de creatina mediante resonancia magnética conespectroscopia . La confirmación diagnóstica en las deficiencias deAGAT y GAMT se realiza determinando la actividad enzimática enfibroblastos o linfoblastos, o la incorporación de creatina para elestudio del defecto de transporte. El estudio de las mutaciones en losgenes AGAT, GAMT (herencia autonómica recesiva) y SLC6A8(ligado al cromosoma X) completa el diagnóstico. Conclusiones.Los síndromes de deficiencia de creatina cerebral están asociadosprincipalmente al retraso mental y al autismo. Las deficiencias deGAMT y AGAT responden al tratamiento con creatina, mientrasque los pacientes con defectos en el transporte no responden a estaterapia, por lo que se están evaluando nuevas aproximaciones terapéuticaspara esta enfermedad

[Diagnosis and treatment of brain creatine deficiency syndromes]. / Diagnostico y tratamiento de los sindromes de deficiencia de creatina cerebral.

AIM: To review the clinical, biochemical and genetic aspects of brain creatine deficiency syndromes, as well as the therapeutic options available. DEVELOPMENT: Brain creatine deficiency syndrome has recently been described as a series of inborn errors of metabolism that affect the synthesis and transport of creatine. Three metabolic defects are known: two affect synthesis -guanidinoacetate methyltransferase (GAMT) and arginine:glycine amidinotransferase (AGAT)- and one affects the transport of creatine. Clinically, these patients can display mental retardation, language disorders, epilepsy, autistic behaviour, neurological impairment and movement disorders. After the clinical selection, the different defects can be identified by a biochemical study involving the analysis of metabolites in biological fluids (guanidinoacetate and creatine/ creatinine ratio). Before continuing with the molecular studies, it is important to confirm the deficiency of brain creatine by means of magnetic resonance imaging with spectroscopy. Diagnostic confirmation of AGAT and GAMT deficits is carried out by determining the enzymatic activity in fibroblasts or lymphoblasts, or the incorporation of creatine in the case of studies of transport defects. The study of mutations in AGAT, GAMT (autosomal recessive inheritance) and SLC6A8 (X-linked) genes completes the diagnosis. CONCLUSIONS: Brain creatine deficiency syndromes are mainly associated to mental retardation and autism. GAMT and AGAT deficiencies respond to treatment with creatine, whereas patients with transport defects do not respond to this therapy; new therapeutic approaches are therefore being evaluated for this disease.