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Table of Contents    
LETTER TO EDITOR
Year : 2021  |  Volume : 69  |  Issue : 1  |  Page : 219-221

Novel Compound Heterozygous SACS Mutations in a Case with a Spasticity-Lacking Phenotype of Sacsin-Related Ataxia


1 Department of Neurology; Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
2 Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine; Intensive Care Unit, Zhejiang Hospital, Hangzhou, Zhejiang, China
3 Department of Neurology, The Second Affiliated Hospital; Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
4 Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

Date of Submission28-Oct-2018
Date of Decision10-Nov-2019
Date of Acceptance03-Nov-2019
Date of Web Publication24-Feb-2021

Correspondence Address:
Wei Luo
Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou - 310009, Zhejiang
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.310115

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How to cite this article:
Chen Y, Cen Z, Zheng X, Chen S, Xie F, Luo W. Novel Compound Heterozygous SACS Mutations in a Case with a Spasticity-Lacking Phenotype of Sacsin-Related Ataxia. Neurol India 2021;69:219-21

How to cite this URL:
Chen Y, Cen Z, Zheng X, Chen S, Xie F, Luo W. Novel Compound Heterozygous SACS Mutations in a Case with a Spasticity-Lacking Phenotype of Sacsin-Related Ataxia. Neurol India [serial online] 2021 [cited 2021 Apr 11];69:219-21. Available from: https://www.neurologyindia.com/text.asp?2021/69/1/219/310115




Dear Editors,

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS, MIM#270550) is an inherited neurodegenerative disorder first described among French Canadians in the Charlevoix-Saguenay region of Quebec, with a homogeneous clinical picture characterized by a triad of early-onset cerebellar ataxia, peripheral neuropathy, and lower limb spasticity.[1]

Here, we report a case caused by novel compound heterozygous SACS mutations, presenting without lower limb spasticity, usually a core feature of ARSACS.

The 30-year-old Chinese male patient (II: 2) [Figure 1]a was referred to our clinic for evaluation of progressive ataxia in 2017. He learned to walk at 2 years of age and slowly developed progressive cerebellar symptoms primarily affecting gait. There was no known family history of similar symptoms.
Figure 1: (a) Family pedigree: The proband was a compound heterozygote for these two novel SACS mutations. Both his father and elder sister harbored one heterozygous mutation (c. 8000T > C, p.F2667S). His mother carried the other heterozygous mutation (c. 10685_10689del, p.F3562*). (b) Sequence chromatograms of the proband with an arrow (black) indicating the frameshift mutation and an arrow (red) indicating the missense mutation, along with corresponding control sequences (wt1 and wt2). (c) Multiple sequence alignment showing strict conservation across species at the affected amino acid residue 2667

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Neurological examination showed symmetrical muscle atrophy in distal upper limbs. Dysarthria, dysmetria, steppage gait, and pes cavus were also observed. Deep tendon reflexes of the upper limbs and knees were normal but ankle reflexes were absent. The muscle tension and sense were normal in all extremities. Questionable Babinski signs were noted bilaterally.

Electrophysiological studies revealed a mixed demyelinating and axonal neuropathy. Brain MRI revealed characteristic atrophy of the vermis superior and cerebellar hemisphere as well as pontine hypointensities on T2-weighted images. Supratentorial changes were also noteworthy with mild atrophy of the cerebral cortex including the frontal and parietal lobes as well as slight thinning of the corpus callosum [Figure 2].
Figure 2: Brain MRI of the proband showed the atrophy of the cerebellum and slight thinning of the corpus callosum on T2-weighted sagittal image (a) and linear pontine hypointensities on T2-weighted axial image (b) and FLAIR axial image (c), atrophy of the frontal and parietal lobe on T2-weighted sagittal image (d)

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Genetic screening of the proband for SCA types 1, 2, 3, 6, 7, 8, 12, 17, and DRPLA did not reveal pathogenic repeat expansions. Whole exome sequencing identified two novel heterozygous mutations in the gene SACS (NM_014363) – one frameshift mutation (c.10685_10689del, p.F3562*) and one missense mutation (c.8000T>C, p.F2667S) [Figure 1]b. Both mutations were not found in the 1000 Genomes (Phase 3), dbSNP v. 151, Genome Aggregation Database (gnomAD r2.0.2), the professional version of HGMD (2018.1). The frameshift mutation was predicted to result in a strongly truncated protein and the loss of two highly conserved domains: DnaJ and HEPN, critical to the function of the sacsin protein. The missense mutation was conserved across species [Figure 1]c and [Table 1] and predicted to be disease-causing by multiple in silico tools [Table 1]. Cosegregation analysis [Figure 1]a suggests that the two mutations were located in trans.
Table 1: In silico predictions of the novel missense mutation c.8000T>C (p.F2667S)

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Our case does not present with lower limb spasticity, usually a core feature of ARSACS. There is a possibility that severe peripheral nerve degeneration shown in electrophysiological study can mask any spasticity in our case. Testing for the SACS gene should, therefore, be taken into consideration even in cases with the lack of one or two cardinal features of the clinical triad.

Financial support and sponsorship

This study was supported by the National Natural Science Foundation of China (Proj., No. 81571089, No. 81371266 and No. 81600850).

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bouchard JP, Barbeau A, Bouchard R, Bouchard RW. Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Can J Neurol Sci 1978;5:61-9.  Back to cited text no. 1
    


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