Kearns-Sayre syndrome: Cerebral folate deficiency, MRI findings and new cerebrospinal fluid biochemical features Mercedes Serrano a,b , María Teresa García-Silva b,c , Elena Martin-Hernandez b,c , Maria del Mar O’Callaghan a,b , Pilar Quijada b,c , Ana Martinez-Aragón b,c , Aida Ormazábal a,b , Alberto Blázquez b,c , Miguel A. Martín b,c , Paz Briones b,d , Ester López-Gallardo b,e , Eduardo Ruiz-Pesini b,e , Julio Montoya b,e , Rafael Artuch a,b, * , Mercedes Pineda a,b a Neuropediatric and Clinical Biochemistry Departments, Hospital Sant Joan de Déu, Barcelona, Spain b Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Zaragoza and Madrid, Spain c Laboratorio de Enfermedades Mitocondriales, Centro de Investigación. Unidad de Enfermedades Mitocondriales, Departamento de Pediatría y Servicio de Radiología. Hospital Universitario 12 de Octubre, Madrid, Spain d Instituto de Bioquímica Clínica-CSIC. Barcelona, Spain e Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Spain article info Article history: Received 4 October 2009 Received in revised form 5 March 2010 Accepted 2 April 2010 Available online 11 April 2010 Keywords: Biogenic amines Dopamine Folate Kearns-Sayre syndrome Mitochondrial diseases abstract We evaluated cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5-MTHF), biogenic amines, and white matter status in six Kearns-Sayre syndrome (KSS) patients. They presented severe 5-MTHF deficiency. A significant negative correlation was observed between CSF 5-MTHF and protein concentration. CSF homovanillic acid was clearly high. Regarding neuroimaging, the main feature was hyperintensity in the basal ganglia, brainstem, and cerebral/cerebellar white matter. The severity of hemispheric white matter disturbances appeared to be qualitatively associated with 5-MTHF values. The negative correla- tion between 5-MTHF and proteins supports the hypothesis of impaired choroid plexus function. Inter- estingly, despite very low 5-MTHF, clearly high neurotransmitter metabolites were found. Ó 2010 Elsevier B.V. and Mitochondria Research Society. All rights reserved. 1. Introduction Kearns-Sayre syndrome (KSS), Pearson’s syndrome and progres- sive external ophthalmoplegia are three overlapping syndromes comprising the so-called mitochondrial DNA deletion syndromes. Pearson syndrome was described in patients presenting refractory sideroblastic anemia and exocrine pancreatic dysfunction (Pearson et al., 1979). Interestingly, some of these patients subsequently de- velop the features of KSS (Larsson et al., 1990; Rotig et al., 1990). KSS is a neurodegenerative multisystemic disorder that presents before 20 years of age, characterized by pigmentary retinopathy, progressive external ophthalmoparesis, heart block, cerebellar ataxia, and high cerebrospinal fluid (CSF) protein concentration (Zeviani et al., 1988), this last reflecting impaired protein transport across choroid plexus. It has been suggested that an energetic de- fect in choroid plexus due to accumulation of mutated mitochon- drial DNA copies could cause this biochemical alteration, but so too could a severe 5-methyltetrahydrofolate (5-MTHF) deficiency in KSS patients (Allen et al., 1983; Pineda et al., 2006; Tanji et al., 2000). 5-MTHF is the most important methyl donor for methylation reactions (through S-adenosylmethionine) and it is involved in more than 100 metabolic steps (Hyland et al., 1988; Surtees et al., 1994). Among them, folate seems essential for methylation and stability of myelin (Pineda et al., 2006). Moreover, it is also related with dopamine and serotonin turnover through tetrahy- drobiopterin (BH 4 ) de novo biosynthesis and salvage pathways. Furthermore, 5-MTHF is also involved in methylation of biogenic amines through cathecol-O-methyltransferase (Botez et al., 1982; Hyland et al., 1988; Surtees et al., 1994). Low 5-MTHF values may therefore lead to white matter lesions and to impairment in both pterins and biogenic amine status. 1567-7249/$ - see front matter Ó 2010 Elsevier B.V. and Mitochondria Research Society. All rights reserved. doi:10.1016/j.mito.2010.04.001 Abbreviations: BH 4 , tetrahydrobiopterin; CSF, cerebrospinal fluid; 5-HIAA, 5-hydroxyindoleacetic acid; HPLC, high performance liquid chromatography; HVA, homovanillic acid; KSS, Kearns-Sayre syndrome; 5-MTHF, 5-methyltetrahy- drofolate; 5-MTHFR, 5-methyltetrahydrofolate reductase. * Corresponding author at: Clinical Biochemistry Department, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2. 08950 Esplugues, Barcelona. Tel.: +34 93 253 2100; fax: +34 93 280 3626. E-mail address: rartuch@hsjdbcn.org (R. Artuch). Mitochondrion 10 (2010) 429–432 Contents lists available at ScienceDirect Mitochondrion journal homepage: www.elsevier.com/locate/mito