Brain Advance Access originally published online on January 19, 2009
Brain 2009 132(3):801-809; doi:10.1093/brain/awn355
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Cerebellar ataxia with elevated cerebrospinal free sialic acid (CAFSA)
1 INSERM UMR S679, Hôpital de la Salpêtrière, Paris, France 2 Institute of Metabolic Disease, Baylor Research Institute, Dallas, USA 3 Fédération des Maladies du Système Nerveux and Reference Center for Lysosomal diseases, Hôpital de la Salpêtrière, Paris, France 4 Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine, Washington, DC, USA 5 Radboud University Nijmegen Medical Center, Laboratory of Pediatrics and Neurology, Nijmegen, The Netherlands, 6 INSERM U927, Université de Poitiers, Hôpital La Milêtrie, Poitiers, France 7 Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA 8 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands 9 Radboud University Nijmegen Medical Center, Department of Neurology, Nijmegen, The Netherlands 10 Département de Génétique et Cytogénétique, Hôpital de la Salpêtrière, Paris, France 11 INSERM U820, Faculté de Médecine Lyon-RTH Laennec, Lyon, France
Correspondence to: Dr Fanny Mochel, INSERM UMR S679, Hôpital La Salpêtrière, 47 Bld de l'Hôpital, Bâtiment Nouvelle Pharmacie - 4ème étage, 75013 Paris, France E-mail: fanny.mochel{at}upmc.fr
In order to identify new metabolic abnormalities in patients with complex neurodegenerative disorders of unknown aetiology, we performed high resolution in vitro proton nuclear magnetic resonance spectroscopy on patient cerebrospinal fluid (CSF) samples. We identified five adult patients, including two sisters, with significantly elevated free sialic acid in the CSF compared to both the cohort of patients with diseases of unknown aetiology (n = 144; P < 0.001) and a control group of patients with well-defined diseases (n = 91; P < 0.001). All five patients displayed cerebellar ataxia, with peripheral neuropathy and cognitive decline or noteworthy behavioural changes. Cerebral MRI showed mild to moderate cerebellar atrophy (5/5) as well as white matter abnormalities in the cerebellum including the peridentate region (4/5), and at the periventricular level (3/5). Two-dimensional gel analyses revealed significant hyposialylation of transferrin in CSF of all patients compared to age-matched controls (P < 0.001)—a finding not present in the CSF of patients with Salla disease, the most common free sialic acid storage disorder. Free sialic acid content was normal in patients’ urine and cultured fibroblasts as were plasma glycosylation patterns of transferrin. Analysis of the ganglioside profile in peripheral nerve biopsies of two out of five patients was also normal. Sequencing of four candidate genes in the free sialic acid biosynthetic pathway did not reveal any mutation. We therefore identified a new free sialic acid syndrome in which cerebellar ataxia is the leading symptom. The term CAFSA is suggested (cerebellar ataxia with free sialic acid).
Key Words: cerebellar ataxia; free sialic acid; cerebrospinal fluid; neurometabolic disorder; nuclear magnetic resonance spectroscopy
Abbreviations: CAFSA, cerebellar ataxia with free sialic acid; CMAS, CMP-Neu5Ac synthase; CSF, cerebrospinal fluid; HIBM, hereditary inclusion body myopathy; Neu5Ac, N-acetylneuraminic acid; NMRS, nuclear magnetic resonance spectroscopy; NPL, Neu5Ac pyruvate lyase; SASD, free sialic acid storage diseases
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Received November 10, 2008. Revised November 28, 2008. Accepted December 2, 2008.
*These authors contributed equally to this study.