Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum

Abstract

BackgroundMutations in SACS, leading to autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), have been identified as a frequent cause of recessive early-onset ataxia around the world. Here we aimed to enlarge the spectrum of SACS mutations outside Quebec, to establish the pathogenicity of novel variants, and to expand the clinical and imaging phenotype.MethodsSequencing of SACS in 22 patients with unexplained early-onset ataxia, assessment of novel SACS variants in 3.500 European control chromosomes and extensive phenotypic investigations of all SACS carriers.ResultsWe identified 11 index patients harbouring 17 novel SACS variants. 9/11 patients harboured two variants of at least probable pathogenicity which were not observed in controls and, in case of missense mutations, were located in highly conserved domains. These 9 patients accounted for at least 11% (9/83) in our series of unexplained early onset ataxia subjects. While most patients (7/9) showed the classical ARSACS triad, the presenting phenotype reached from pure neuropathy (leading to the initial diagnosis of Charcot-Marie-Tooth disease) in one subject to the absence of any signs of neuropathy in another. In contrast to its name “spastic ataxia”, neither spasticity (absent in 2/9=22%) nor extensor plantar response (absent in 3/9=33%) nor cerebellar ataxia (absent in 1/9=11%) were obligate features. Autonomic features included urine urge incontinence and erectile dysfunction. Apart from the well-established MRI finding of pontine hypointensities, all patients (100%) showed hyperintensities of the lateral pons merging into the (thickened) middle cerebellar peduncles. In addition, 63% exhibited bilateral parietal cerebral atrophy, and 63% a short circumscribed thinning of the posterior midbody of the corpus callosum. In 2 further patients with differences in important clinical features, VUS class 3 variants (c.1373C>T [p.Thr458Ile] and c.2983 G>T [p.Val995Phe]) were identified. These variants were, however, also observed in controls, thus questioning their pathogenic relevance.ConclusionsWe here demonstrate that each feature of the classical ARSACS triad (cerebellar ataxia, spasticity and peripheral neuropathy) might be missing in ARSACS. Nevertheless, characteristic MRI features – which also extend to supratentorial regions and involve the cerebral cortex – will help to establish the diagnosis in most cases.

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

“…Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay (ARSACS) (OMIM phenotype #270550) shows a challenging phenotypic overlap with HSP and HA, with a remarkable clinical diversity. [20][21][22] ALS2 (Alsin) (OMIM gene *606352) is another prominent example of a gene implicated in pyramidal syndromes, with overlapping roles in other neurodegenerative conditions including amyotrophic lateral sclerosis. 23 Relatively little is known about the genetics of spinocerebellar degenerations in the Sudanese population.…”

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

“…Recent descriptions of ARSACS outside Québec also reported normal retinal fibres [7,10]. Neuropathy usually presents after the 2 nd decade of life and progresses to spastic paraparesis; [9] in that case, the authors highlight the early onset of neuropathy, with rapidly progressive distal weakness, resulting in loss autonomous gait.…”

“…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.…”

“…Classical clinical features include slowly progressive, early-onset (age 12-18 months), cerebellar ataxia,[8] sensory-motor neuropathy, pyramidal tract signs, finger and feet deformities, nystagmus and hypermyelination of retinal nerve fibres [9][10][11][12]. Cognition is usually preserved.…”

“…Cognition is usually preserved. Bladder and bowel symptoms have been commonly described, but not well-studied [4,10,12]. Recent reports on new phenotypic variants of ARSACS make the clinical diagnosis even more challenging [13,14].…”