Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder caused by biallelic mutations in the SACS gene. Once thought to be limited to Charlevoix-Saguenay region of Quebec, recent evidence has indicated that this disorder is present worldwide. It is classically characterized by the triad of ataxia, pyramidal involvement, and axonal-demyelinating sensorimotor neuropathy. However, diverse clinical features have been reported to be associated with this disorder. In this report, we present the first Iranian family affected by ARSACS with unique clinical features (mirror movements, hypokinesia/bradykinesia, and rigidity) harboring a novel deletion mutation in the SACS gene. Our findings expand the genetic and phenotypic spectrum of this disorder.

Spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare autosomal recessive neurodegenerative disease related to SACS gene and characterized by cerebellar, pyramidal and some other signs. The disease was delineated in Quebec, where it cumulates due to founder effect and has similar phenotype with very early onset. ARSACS in other populations is more variable. The first Russian case of ARSACS in a 37-year-old woman, an only patient in a Lak (one of Dagestan ethnicities) family, is presented. Along with main typical features, she had atypical late disease onset (in 32 years) and moderate cognitive decline. MPS-panel \'hereditary paraplegias\' detected an earlier reported homo- or hemizygous mutation c.72276C>T (p.Arg2426Stop) in SACS exon 10.
Спастическая атаксия Шарлевуа-Сагенэ (ARSACS) - редкая аутосомно-рецессивная нейродегенерация с сочетанной мозжечковой и пирамидной симптоматикой и рядом других симптомов, вызываемая мутациями гена SACS. Болезнь, описанная в Квебеке (франкоязычная провинция Канады), где накопление заболевания связано с эффектом основателя, характеризуется однотипной картиной, в частности, ее ранним началом. Случаи в других популяциях имеют большее разнообразие. Представлено первое российское наблюдение у женщины 37 лет, единственной больной в дагестанской (лакской) неинбредной семье. При основных характерных симптомах атипичными были позднее начало (в 32 года) и умеренные когнитивные расстройства. Экзомное секвенирование (панель \'спастические параплегии\') выявило в экзоне 10 гена SACS ранее описанную мутацию c.72276C>T (p.Arg2426Stop) в гомозиготном или гемизиготном состоянии.