New findings in the ataxia of Charlevoix–Saguenay

Abstract

The aim of the study was to enhance our understanding of the pathogenesis of the ataxia of Charlevoix-Saguenay, based on the findings presented herein. Five patients with a molecular diagnosis of this disease underwent clinical, radiological, ophthalmologic and electrophysiological examinations. Five novel mutations, which included nonsense and missense variants, were identified, with these resulting in milder phenotypes. In addition to the usual manifestations, a straight dorsal spine was found in every case, and imaging techniques showed loss of the dorsal kyphosis. Cranial MRI demonstrated hypointense linear striations at the pons. Tensor diffusion MRI sequences revealed that these striations corresponded with hyperplastic pontocerebellar fibres, and tractographic sequences showed interrupted pyramidal tracts at the pons. Ocular coherence tomography demonstrated abnormal thickness of the nerve fibre layer. Electrophysiological studies showed nerve conduction abnormalities compatible with a dysmyelinating neuropathy, with signs of chronic denervation in distal muscles. The authors suggest that the hyperplastic pontocerebellar fibres compress the pyramidal tracts at the pons, and that the amount of retinal fibres traversing the optic discs is enlarged. These facts point to the contribution of an abnormal developmental mechanism in the ataxia of Charlevoix-Saguenay. Accordingly, spasticity would be mediated by compression of the pyramidal tracts, neuromuscular symptoms by secondary axonal degeneration superimposed on the peripheral myelinopathy, while the cause of the progressive ataxia remains speculative. The distinctive aspect of the dorsal spine could be of help in the clinical diagnosis.

Assessment of Whole-Brain White Matter by DTI in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

“…Three major results, which confirm and add to previous findings [10][11][12] , can be derived from our data: 1) Large TPF with increased FA and AD and decreased RD squeezed and displaced the pontine CST with decreased FA, increased RD, and increased mean diffusivity, as was also observed on tractography.…”

“…Supporting our nerve conduction studies and DTI findings, previous nerve conduction studies and sural nerve biopsy examinations also revealed demyelinating neuropathy with superimposed axonal involvement in patients with ARSACS. 11,[21][22][23] Severe CST involvement, as assessed by motor-evoked potential abnormalities, was attributed to the demyelination of the CST in an autopsy study. 24 Our current TBSS study, on the contrary, points out both axonal and myelin damage in the CST.…”

“…7 By measuring anisotropic diffusion of water in the WM, DTI detects abnormalities in the myelin, axon, or orientation of fibers within the bundle. 8,9 Gazulla et al 10,11 described nonquantitative abnormalities of the TPF and CST by DTI in 2 studies with 5 patients. These authors suggested a developmental basis for ARSACS by showing interruption of the CST in the pons by large TPF.…”

Inherited Cerebellar Ataxia in Childhood: A Pattern-Recognition Approach Using Brain MRI

“…25 Recently, some reports have suggested that iron deposition and consequent T2 hy- pointensity resulting from magnetic susceptibility differences can occur in Friedrich ataxia, and a pattern of linear T2 hypointensity in the pons was described in patients with AR ataxia of CharlevoixSaguenay. 16,[26][27][28][29] If T1 hyperintensity of the globus pallidus is associated with childhood ataxia, Wilson disease should be considered.…”

Autosomal recessive spastic ataxia of Charlevoix-Saguenay in a Portuguese child caused by a novel SACS mutation

“…In a study of 164 alleles of patients with ARSACS born in Québec, Richter et al (1999) reported that 92.6% cases were homozygous for the 6594 deletion [20]. Since the discovery of the gene responsible for ARSACS, more than 100 disease-causing genetic variants have been described around the world [7,10,12,21]. The authors present a case of a novel mutation related to ARSACS, in a Portuguese child.…”