Elevated Sialic Acid Linked to Cerebellar Ataxia
ARTICLE IN BRIEF
French investigators identified a previously unknown syndrome in five of 25 cerebellar patients associated with elevated free sialic acid in the CSF.
SEATTLE—The leader of an international study linking one in five cases of cerebellar ataxia to elevations of free sialic acid in the CSF called on neurologists to consider sending samples of CSF to her laboratory for testing.
The study, published online Jan. 19 in advance of the March edition of the journal Brain and described during a science program at the AAN annual meeting here, used a novel technique to identify the previously unknown syndrome in five of 25 cerebellar patients of unknown etiology screened. The authors offered the name CAFSA (cerebellar ataxia with free sialic acid) for the syndrome.
Besides cerebellar ataxia, a distinct phenotype emerged in the screening process: all five CAFSA patients had onset of ataxia in early adult years, with peripheral neuropathy and cognitive decline or behavioral changes. MRI revealed mild to moderate cerebellar atrophy in all five, as well as white matter abnormalities in the cerebellum including the region of the dentate nucleus in four of five, and at the periventricular level in three of five.
“We suspect it is genetic because we found a family with two affected sisters,” said the lead author Fanny Mochel, MD, a geneticist and metabolician in the French research institute, INSERM, at the Hôpital La Salpêtrière in Paris, and a doctoral candidate in neuroscience at Baylor College of Medicine.
“The problem is that we have no other families with more than one affected person,” she said. “What will help tremendously is to find other families with more than one (symptomatic) person, especially if there is co-segregation, so that we can do genetic linkage studies.”
Dr. Mochel noted that CAFSA is distinct from Salla disease, the most common free sialic acid storage disorder, in several ways: age of onset of cerebellar ataxia in Salla disease occurs in infancy to early childhood, while onset in CAFSA generally occurs between 10 to 24 years, and Salla is associated with nystagmus and pyramidal syndrome, which does not occur with CAFSA. In addition, CAFSA patients are normal initially cognitively and then decline, while Salla have mental retardation (congenital). The MRI for Salla patients shows marked cerebellar atrophy — which is only mild to moderate in CAFSA — thin corpus callosum and diffuse hypomyelination. Of importance free sialic acid is elevated in the urine and fibroblasts of patients with Salla, but not in those with CAFSA. Altogether, the overlap is free sialic acid elevation in CSF and cerebellar ataxia clinically.
While offering no effective treatment yet, the study is important for uncovering a novel pathway that might open the way to therapy. “This paper was very interesting to me because ataxia is a heterogeneous condition,” said Fuki M. Hisama, MD, a neurogeneticist at Children's Hospital Boston and Harvard Medical School.
“Although we know a lot about the underlying genetic basis of adult-onset dominant forms, there is a lot less that's understood about the recessive forms, both in adults and children. They still haven't found what causes the elevated sialic acid, but the importance of the paper is that they applied a highly specific biochemical method to implicate a new pathway in ataxia.”
Dr. Mochel collaborated with researchers in France, the Netherlands, and the US to perform in-vitro proton nuclear magnetic resonance spectroscopy on CSF from 144 patients with complex neurodegenerative disorders of unknown etiology, as well as a control group of 91 patients with well-defined diseases. CSF from five of the 25 patients with ataxia of unknown etiology turned out to have high levels of free sialic acid, a monosaccharide that is an important component of glycoproteins and glycolipids, and therefore of cellular membranes.
A sixth CAFSA patient was also identified. Sequencing four candidate genes in the free sialic acid biosynthetic pathway did not reveal any mutation, but Dr. Mochel said that once the mutated gene is identified, its role should be apparent.
“Unlike many genetic conditions, when we do figure out what the mutated gene is, we already know what the pathway is,” she said. “We don't think it is the free sialic acid itself that is necessarily the problem, but we may be wrong. It may be another issue, like one of these enzymes that doesn't attach the free sialic acid to proteins. In that case, we could work on providing the missing enzyme.”
Two-dimensional gel analyses revealed significant hyposialylation of transferrin in CSF from all five CAFSA patients compared to age-matched controls (p < 0.001). Furthermore, the free sialic acid content was normal in patients' urine and cultured fibroblasts, as were plasma glycosylation patterns of transferrin. Ganglioside analysis in peripheral nerve biopsies of two of the five patients were tested and had normal patterns.
Dr. Mochel's group used MRI to conduct spectroscopy analysis of the CSF samples rather than of patients, a technique which is currently used in very few European centers, and none in the US, to her knowledge. That is why the different European and American collaborators involved in this study are now developing a method to measure free sialic acid by mass spectrometry, a biochemical technique available in most academic centers. “Altogether now we have analyzed 400 samples,” she said. “If you think about it, worldwide there could be dozens more cases of CAFSA.” •
Lead investigator Fran Mochel, MD, invited neurologists with all cerebellar ataxia patients of unknown origin, regardless of apparent phenotype, to contact her at firstname.lastname@example.org about the possibility of having her group conduct the inexpensive and rapid test of CSF samples.