Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Abstract

SUMMARY:A new syndrome of autosomal recessive spastic ataxia has been isolated in the Charlevoix-Saguenay region of Quebec. This syndrome is remarkably homogeneous and includes: spasticity, dysarthria, distal muscle wasting, foot deformities, truncal ataxia, absence of sensory evoked potentials in the lower limbs, retinal striation reminiscent of early Leber's atrophy and the frequent presence (57%) of a prolapse of the mitral valve. Biochemically, many cases show impaired pyruvate oxidation, others have hyperbilirubinaemia and some have low serum β-lipoproteins and HDL apoproteins. These features are similar to those found in trypical Friedreich's ataxia.

New findings in the ataxia of Charlevoix–Saguenay

“…In addition to the well-known skeletal abnormalities of pes cavus and hammertoes [8], an alteration of the dorsal kyphosis was observed in every patient presented herein. The dorsal spine appeared straight, and the posterior rib cage flat; and despite an absence of muscle weakness, the superior angles of the scapulae stuck out from the thoracic wall, exhibiting the peculiar appearance shown in Fig.…”

“…Thus, the increased amount of pontocerebellar fibres detected in our patients does not suggest a degenerative origin, but would be more evocative of a developmental one. In this case, the pontocerebellar fibres would compress the pyramidal tracts at the pons since the embryonic period, causing spasticity from a very early age, as reported [7][8][9][10]. Although the corticospinal tracts were reported to be small at the pons in ARSACS, and the pontine nuclei, preserved, the pontocerebellar fibres were not detailed [7,9,10].…”

“…ARSACS usually presents with early onset lower-limb spasticity, cerebellar ataxia, peripheral neuropathy, and skeletal and retinal anomalies [7,8,10,31], in spite of cases with incomplete clinical expression [34] or late onset [5]. Although the resulting clinical picture is easily recognizable, some aspects of the disease need to be defined better, as will be considered below.…”

“…Taking into account the increased amount of pontocerebellar fibres found in the images presented herein, it is plausible that glutamate excitotoxicity could bring about neuronal death in the cerebellar cortex [2,21,32]. This phenomenon could be responsible for the cerebellar atrophy evident on MRI scans, and for the progressive ataxia associated with ARSACS, of more tardive appearance than spasticity [7][8][9][10]. Damage to the spinocerebellar tracts and the proprioceptive pathways could contribute to the genesis of the ataxia, as well.…”

Sacsin-related ataxia caused by the novel nonsense mutation Arg4325X

“…ARSACS was originally described in the Charlevoix-Saguenay region, in northeastern Quebec, and it has been considered to be a genetic disorder confined to French Canadians [1]. Since the SACS gene responsible for ARS-ACS was reported to have a single giant exon encoding a 3829-amino-acid protein, sacsin [4], novel mutations have been reported during the past 2 years in Tunisia [5], Italy [2,6], Turkey [9], Japan [7,8,10,11] and Spain [3].…”