title: Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome.
abstract: BACKGROUND
  Kearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy.
  
  
  METHODS
  
  
  
  METHODS
  We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Déu Hospital. Two patients refused to participate in the treatment protocol.
  
  
  METHODS
  Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot.
  
  
  METHODS
  The follow-up periods ranged from one to eight years. Cases 1-4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day.
  
  
  RESULTS
  No adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients. Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy.
  
  
  CONCLUSIONS
  Four patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS.
  
  
  BACKGROUND
  Eudrac T2007-00-6748-23.
authors.affiliation: Unidad de Enfermedades Mitocondriales-Enfermedades Metabólicas Hereditarias. Dpto. de Pediatría y Radiología, Hospital 12 de Octubre, Madrid, Spain. pilar.quijada@gmail.com.
authors.forename: Pilar
authors.initials: P
authors.lastname: Quijada-Fraile
authors.affiliation: Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues, Barcelona, 08950, Spain. mocallaghan@hsjdbcn.org.
authors.forename: Mar
authors.initials: M
authors.lastname: O'Callaghan
authors.affiliation: Unidad de Enfermedades Mitocondriales-Enfermedades Metabólicas Hereditarias. Dpto. de Pediatría y Radiología, Hospital 12 de Octubre, Madrid, Spain. emartinhernandez@salud.madrid.org.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-Hernández
authors.affiliation: Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III, Madrid, Spain. rmontero@hsjdbcn.org.|Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues, Barcelona, 08950, Spain. rmontero@hsjdbcn.org.
authors.forename: Raquel
authors.initials: R
authors.lastname: Montero
authors.affiliation: Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III, Madrid, Spain. agarcia@hsjdbcn.org.|Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues, Barcelona, 08950, Spain. agarcia@hsjdbcn.org.
authors.forename: Àngels
authors.initials: À
authors.lastname: Garcia-Cazorla
authors.affiliation: Unidad de Enfermedades Mitocondriales-Enfermedades Metabólicas Hereditarias. Dpto. de Pediatría y Radiología, Hospital 12 de Octubre, Madrid, Spain. anmaca7@gmail.com.
authors.forename: Ana Martínez
authors.initials: AM
authors.lastname: de Aragón
authors.affiliation: Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues, Barcelona, 08950, Spain. jmucart@hsjdbcn.org.
authors.forename: Jordi
authors.initials: J
authors.lastname: Muchart
authors.affiliation: Servicio de Pediatría, Hospital Universitario Central de Asturias, Oviedo, Spain. neuropediatria.huca@gmail.com.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Málaga
authors.affiliation: Servicios de Pediatría y Radiología, Hospital de Cabueñes, Asturias, Spain. neurocabuenes@hotmail.es.
authors.forename: Rafael
authors.initials: R
authors.lastname: Pardo
authors.affiliation: Servicios de Pediatría y Radiología, Hospital de Cabueñes, Asturias, Spain. neurocabuenes@hotmail.es.
authors.forename: Pedro
authors.initials: P
authors.lastname: García-Gonzalez
authors.affiliation: Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues, Barcelona, 08950, Spain. cjou@hsjdbcn.org.
authors.forename: Cristina
authors.initials: C
authors.lastname: Jou
authors.affiliation: Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III, Madrid, Spain. jmontoya@unizar.es.|Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain. jmontoya@unizar.es.
authors.forename: Julio
authors.initials: J
authors.lastname: Montoya
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain. seortiz@unizar.es.
authors.forename: Sonia
authors.initials: S
authors.lastname: Emperador
authors.affiliation: Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III, Madrid, Spain. eduruiz@unizar.es.|Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain. eduruiz@unizar.es.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ruiz-Pesini
authors.affiliation: Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III, Madrid, Spain. joaquin.arenas@salud.madrid.org.|Mitochondrial Diseases Laboratory, Hospital 12 de Octubre Research Institute (i + 12), Madrid, Spain. joaquin.arenas@salud.madrid.org.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arenas
authors.affiliation: Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III, Madrid, Spain. mamcasanueva.h12o@gmail.com.|Mitochondrial Diseases Laboratory, Hospital 12 de Octubre Research Institute (i + 12), Madrid, Spain. mamcasanueva.h12o@gmail.com.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Martin
authors.affiliation: Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III, Madrid, Spain. aormazabal@hsjdbcn.org.|Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues, Barcelona, 08950, Spain. aormazabal@hsjdbcn.org.
authors.forename: Aida
authors.initials: A
authors.lastname: Ormazabal
authors.affiliation: Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III, Madrid, Spain. pineda@hsjdbcn.org.|Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues, Barcelona, 08950, Spain. pineda@hsjdbcn.org.
authors.forename: Mercè
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Unidad de Enfermedades Mitocondriales-Enfermedades Metabólicas Hereditarias. Dpto. de Pediatría y Radiología, Hospital 12 de Octubre, Madrid, Spain. mgarciasilva@salud.madrid.org.|Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III, Madrid, Spain. mgarciasilva@salud.madrid.org.
authors.forename: María T
authors.initials: MT
authors.lastname: García-Silva
authors.affiliation: Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III, Madrid, Spain. rartuch@hsjdbcn.org.|Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues, Barcelona, 08950, Spain. rartuch@hsjdbcn.org.
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000378:metabolism*; D002648:Child; D019587:Dietary Supplements; D005260:Female; D005494:Folic Acid Deficiency / Q000178:diet therapy / Q000378:metabolism*; D005500:Follow-Up Studies; D006801:Humans; D007625:Kearns-Sayre Syndrome / Q000178:diet therapy / Q000378:metabolism*; D002955:Leucovorin / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D014803:Vitamin B Complex / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D014803:Vitamin B Complex; D002955:Leucovorin