Cerebellar ataxia with elevated cerebrospinal free sialic acid (CAFSA)

Abstract

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).

Elevated CSF N -acetylaspartylglutamate in patients with free sialic acid storage diseases

“…6 However, CSF NAAG was normal in a large cohort of patients with nonneurodegenerative neurologic conditions or white matter disease of other origin. 7 Despite what has been suggested in Pelizaeus-Merzbacher disease, 4 there seems to be no correlation between the levels of NAAG in patients' CSF and the severity of the SASD phenotype in our patient cohort. Interestingly, levels of free sialic acid do not correlate with clinical severity of SASD either.…”

Lipidomic analysis of cerebrospinal fluid by mass spectrometry–based methods

“…Indeed, CSF analysis by high-resolution in vitro proton nuclear magnetic resonance spectroscopy recently allowed the discovery of a potentially novel metabolic disorder in a group of adult patients with unexplained encephalopathies (Mochel et al 2009). Nevertheless, CSF metabolomics studies remain challenging because a large number of metabolites and lipids of interest are expected to occur at concentrations below the practical detection threshold (i.e., the micromolar range), hence limiting the number of CSF metabolites suitable for analysis.…”

Mucopolysaccharidoses and Oligosaccharidoses

“…In these patients free sialic acid was increased in CSF, but in contrast urinary excretion of free sialic acid was normal when tested on several occasions by different methods. Finally, cerebellar ataxia with elevated CSF free sialic acid (CAFSA) has been reported in five patients who in addition to the ataxia had peripheral neuropathy and cognitive decline [11]. The molecular basis of this new disease is yet to be established.…”