RESULTS
We identified 7 patients (4 males) with genetically proven ARSACS with a median age at onset of 5 years (3–7 years) and duration of illness of 20.5 years (10–35 years). The clinical, imaging, electrophysiological, genetic, treatment, and follow-up details are summarized in
Supplementary Table 1 (in the online-only Data Supplement). The MRI findings of 6 patients are provided in
Figure 1 and the clinical examination videos of 2 patients are provided as
Supplementary Video 1 (in the online-only Data Supplement) (patient-2) and
Supplementary Video 2 (in the online-only Data Supplement) (patient-4).
- Clinical details
Walking difficulty (7/7) was the most common presenting symptom. Patients also experienced slurring of speech (2/7), abnormal posturing of the neck (1/7) and hands (2/7), leg weakness (1/7), and global developmental delay with intellectual disability (2/7). A positive family history of similar clinical findings and consanguineous parentage was noted in 2 and 5 patients, respectively.
All patients had cerebellar and pyramidal involvement. Ataxic dysarthria and appendicular ataxia were noted in all patients, and gait ataxia was noted in 5 patients. Gait was spastic-ataxic in 4 patients, ataxic in 1 patient and spastic in 2 patients. Additionally, cerebellar eye signs were noted in 6 patients (gaze evoked nystagmus: 7/7; dysmetric saccades: 4/7; broken pursuits: 3/7; and ill-sustained upbeat nystagmus: 1/7). All patients had bilateral lower limb (LL) spasticity. In addition, upper limb (UL) spasticity, distal UL hypotonia and distal LL hypotonia were noted in one patient each. Deep tendon reflexes were brisk in all patients, ankle jerk was present in 3 patients but was absent in the other 4 patients. The plantar response was extensor in all patients.
The classical retinal sign of ARSACS, hypermyelinated fibers radiating from the optic disc on fundus examination, was noted in four patients. Other neurological signs noted were cognitive impairment (1 patient), abnormal proprioceptive sensation in LL (2 patients), and dystonia (bilateral hand dystonia: 2 patients; cervical with left-hand dystonia: 1 patient).
- Imaging and electrophysiology
All patients had classical neuroimaging findings of perithalamic T2 hyperintensity, pontine transverse fiber hypointensity with bulky pons, and superior vermian and cerebellar atrophy (
Figure 1). Spinal cord atrophy was noted in 6 patients. All 3 patients with peri-optic disc hypermyelinated nerve fibers had a thickened RNFL on OCT (
Figure 2). Evoked potentials were abnormal in five patients, and NCS revealed LL predominant sensorimotor demyelinating polyneuropathy in all 6 patients who underwent the tests.
- Genetic testing
Exome sequencing of all 7 patients revealed eight unique pathogenic or likely pathogenic variants (homozygous: 6 patients; compound heterozygous: 1 patient) in the SACS gene. Of the eight variants, two variants have been previously described (c.6000_6004del:p.Arg2002CysfsTer25 and c.10686_10689 delCTTT:p.Phe3562LeufsTer8), and the other six variants were novel (c.8240T>A:p.Il2747Asn, c.3810delT:p.Phe1270LeufsTer4, c.13531del:p.Glu4511AsnTer9, c.11356G>T:p.Glu3786Ter, c.13469A>C:p.Tyr4490Ser, and c.1908delG:p.Lys63SerfsTer15).
- Treatment and follow-up
All patients were treated symptomatically with baclofen for spasticity. Amantadine was given to 2 patients for ataxia, and clonazepam was given to 1 patient for dystonia. In addition, all patients received physiotherapy and speech therapy. Follow-up data were available for 5 patients (range: 6–12 months), and four-fifths of the patients noted mild improvement in their symptoms with no new symptoms.
- Review of the literature regarding patients with ARSACS from India
In addition to seven cases from this study, we identified an additional 21 (18 families) cases from 11 publications after removing duplicates (
Supplementary Table 2 in the online-only Data Supplement). The age at onset ranged from 1–37 years, with a first-decade onset noted in approximately two-thirds of the patients (17/27 patients). A total of fifteen-seventeenths of the families for whom data were available belonged to the southern part of India. Walking difficulty was the most common presenting symptom. Spasticity with ataxia was noted in nearly all patients. Hypermyelinated nerve fibers radiating from the optic disc were observed in 8 patients, whereas another 8 patients were reported to have a normal fundus.
NCSs revealed demyelinating neuropathy in more than two-thirds of the patients (16/21 patients) and axonal neuropathy in the remaining patients. On MRI, pontine stripes were noted in all but three patients. Thickened RNFL on OCT was observed in 8 patients, and the data were not available for the remaining patients. In seven of these patients with OCT abnormalities, fundus examination also revealed peripapillary retinal streaks. Genetic testing details were available for 23 families (26 patients), which revealed pathogenic variants in a homozygous state in 18 families, a compound heterozygous state in four families and a heterozygous state in one family. In total, 21 unique variants were identified, of which the c.8793delA variant (5 patients, 5 families), the c.12851_12854del variant (3 patients, 2 families) and the c.10686_10689del variant (2 patients, 2 families) were the only three variants identified in more than one family. All patients harboring the c.8793delA variant were from Kerala. Truncating variants were the most frequent (17/21 variants), constituting 10 frameshift deletion variants, four stop-gain variants and three frameshift duplication variants. The remaining four were missense variants.
DISCUSSION
This study expands the genetic spectrum of ARSACS by reporting six novel variants and adds 7 cases to the literature with detailed descriptions of clinical and investigative findings. Overall, the findings of our study are in accordance with our current understanding of ARSACS [
3-
5]. In line with previous findings, our patients also had predominantly early-onset slowly progressive spastic-ataxic syndrome with demyelination-predominant polyneuropathy, thickened peri-optic disc RNFL, and horizontal pontine stria, among other classical radiological findings. Most of the patients experienced some mild improvement in response to symptomatic medications at the 6–12-month follow-up.
- Clinical profile
ARSACS is usually a disease of first decade onset and can have developmental delays, especially motor delays, that eventually improve with age as milestones are attained slowly. Walking difficulty is one of the most common presenting symptoms [
3]. In addition to ataxia, LL-predominant pyramidal signs are common and are observed in more than three-fourths of cases. However, with disease progression, neuropathy eventually results in the absence of pyramidal signs in LL. Even then, the extensor plantar response may persist, resulting in a phenotype akin to Friedreich’s ataxia (FA), with ataxia, neuropathy and an extensor plantar response. However, peri-optic retinal streaks or thickened peri-optic disc RNFL are observed in more than 50% of patients with ARSACS, and the absence of cardiac involvement and diabetes mellitus helps distinguish it from FA. Additionally, the early first decade of onset of ARSACS is usually too early for FA.
In addition to the usual progressive cerebellar ataxia, peripheral neuropathy, and spasticity in LLs, certain individuals with ARSACS may present with additional features, including hearing impairment, intellectual disability, myoclonic epilepsy, dystonia, dysphagia, and urinary dysfunction [
9-
12]. Patients may have features of long-standing neuropathy [
3,
13]. Four of our patients had mild focal or multifocal dystonia, which was previously reported in ARSACS but in fewer than 10% of cases [
3,
4,
8]. Dysarthria is common and is observed in the majority of cases of varying severity, and patients can experience oculomotor abnormalities, mainly in the form of nystagmus. However, visual impairment, hearing impairment, dysphagia and dysphonia are rare. Some individuals may encounter challenges in school performance, occasionally attributed to mild intellectual disability; however, it is important to note that ARSACS is not associated with severe intellectual disability [
14].
- Investigations
Investigations such as MRI, OCT, and NCS can confirm the diagnosis or provide clues toward the possibility of ARSACS. The combination of horizontal pontine T2/FLAIR hypointense stripes (the tigroid pattern), superior vermian atrophy and bulky pons on brain magnetic resonance images often helps in differentiating ARSACS from other first-decade-onset ataxias [
3,
6]. The thickly myelinated transverse pontocerebellar tracts give rise to pontine striae and bulky pons findings. Other usually observed MRI brain findings are T2/FLAIR hyperintensity of the lateral pons and thalamus, a thickened middle cerebellar peduncle, thinning of the posterior mid-body callosum, parietal atrophy, arachnoid cysts and spinal cord atrophy [
13].
OCT is another imaging modality that is useful in the diagnosis of ARSACS. Clinically, thickened peri-optic RNFLs appear as retinal streaks radiating from the optic disc, and on OCT, they appear as thickened peripapillary RNFLs [
15]. A cutoff value of 119 μm for average peripapillary RNFL thickness was proposed, which has a sensitivity of 100% and specificity of 99.4% [
16]. Fundoscopy can be abnormal in 70% of cases and can be normal despite having a thickened RNFL on OCT. RNFL thickness shares the common pathogenesis of aberrant thickening of nerve fibers, resulting in pontine striae on MRI [
15].
Very few patients with early-onset ataxia can have demyelinating neuropathy, in contrast to the axonal predominance observed in many other causes. Demyelinating sensorimotor neuropathy is identified in the majority of ARSACS cases [
3,
17]. Evoked potentials also demonstrate a slowed conduction time in the form of dispersed and prolonged latency of motor, visual, evoked and somatosensory evoked potentials [
7,
13,
17].
- Genetic testing
ARSACS results from variants in the
SACS gene situated on chromosome 13q12, which is responsible for encoding the 520-kDa protein sacsin [
4]. This protein is expressed predominantly in Purkinje cells and plays a crucial role in regulating intermediate filament assembly and dynamics. Among the more than 700 pathogenic or likely pathogenic variants described, more than 90% are truncating variants (deletion/duplication/splice-site/stop-gain). Our study identified six novel variants (frameshift deletion: 3, stop gain: 1, missense: 2). Multiple studies have failed to identify any definite phenotype‒genotype correlations. A recent study demonstrated that the sacsin level was almost absent in patients with ARSACS irrespective of the underlying variant type. They also demonstrated that cotranslational ubiquitination and degradation of nascent mutant sacsin protein is a novel underlying mechanism in ARSACS instead of mRNA decay, defective translation, or faster posttranslational degradation [
18].
- ARSACS in India
Most of the cases reported from India are from southern India (Kerala, Karnataka, Andhra Pradesh, Tamil Nadu, and Telangana). However, the two large studies are from Kerala [
13] and Karnataka, which can partially explain these findings. The overall findings were in line with those in Western literature. Notably, one variant, c.8793delA, was identified in five unrelated patients, but all 5 patients lived in the same state, Kerala [
13,
19,
20]. None of these patients had apparent parental consanguinity, but four of them had a homozygous state, and two of them had a positive family history, suggesting a high carrier frequency in this region. Further studies are needed to explore the possibility of a common founder variant in this population.
In conclusion, our study expands the genotypic spectrum of ARSACS by reporting six novel disease-causing variants. Moreover, the clinical, radiological and electrophysiological findings are in line with the previous literature, substantiating that the syndrome as a whole is relatively uniform across geography.
Notes
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Conflicts of Interest
The authors have no financial conflicts of interest.
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Funding Statement
Partially funded by Department of Biotechnology, Government of India for funded project (BT/PR26428/MED/12/783/2017).
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Author Contributions
Conceptualization: Mit Ankur Raval, Vikram V Holla, Pramod Kumar Pal.
Data curation: Mit Ankur Raval, Vikram V Holla, Pramod Kumar Pal. Formal analysis: Mit Ankur Raval, Vikram V Holla. Funding acquisition: Nitish Kamble, Babylakshmi Muthusamy, Ravi Yadav, Pramod Kumar Pal. Investigation: all authors. Methodology: all authors. Project administration: Babylakshmi Muthusamy, Ravi Yadav, Pramod Kumar Pal. Resources: all authors. Supervision: Vikram V Holla, Nitish Kamble, Gautham Arunachal, Babylakshmi Muthusamy, Jitender Saini, Ravi Yadav, Pramod Kumar Pal. Validation: Vikram V Holla, Nitish Kamble, Gautham Arunachal, Babylakshmi Muthusamy, Jitender Saini, Ravi Yadav, Pramod Kumar Pal. Visualization: Vikram V Holla, Pramod Kumar Pal. Writing—original draft: Mit Ankur Raval. Writing—review & editing: Vikram V Holla, Nitish Kamble, Gautham Arunachal, Babylakshmi Muthusamy, Jitender Saini, Ravi Yadav, Pramod Kumar Pal.
Figure 1.MRI brain and spinal cord of patient-1 to 5 and patient-7. T1 (C1), T2 (A1, A4, B1, B4, D1, D4, E1–E4, F1, and F4) and FLAIR (A2, A3, B2, B3, C2, C3, D2, D3, F2, and F3) sequences of MRI brain and spinal cord of patients demonstrating superior vermian atrophy, bulky pons, thin corpus callosum (A1, B1, C1, D1, E1, and F1), perithalamic T2/FLAIR hyperintensity (A2, B2, C2, D2, E2, and F2), T2/FLAIR pontine horizontal striae (A3, B3, C3, D3, E3, and F3), and spinal cord atrophy (A4, B4, D4, E4, and F4). FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.
JEE YOUNG LEE
October 03, 2024