Background and Objectives:Few biochemical markers have been identified in spinocerebellar ataxia type 2 (SCA2). This study aimed to determine the levels of neurofilament light (NfL) in patients with SCA2 and identify whether they were associated with disease severity.Methods:Participants were recruited from one medical center in China, and individuals with SCA2 were genetically diagnosed. NfL levels were assessed using the single molecule array method. Disease severity was evaluated using the Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and the Inventory of Non-Ataxia Symptoms (INAS). Cerebellum and brainstem volumes were calculated using neuroimaging measurements. We used Pearson’s correlation and partial correlation for correlation analyses.Results:Forty-nine manifest patients with SCA2, 10 preclinical individuals with SCA2 and 92 controls were enrolled. A high consistency was identified between serum and CSF NfL (r = 0.868, p < 0.0001). In individuals with SCA2, levels of serum NfL were associated with disease severity (SARA, r = 0.425, p = 0.003; ICARS, r = 0.383, p = 0.009; INAS, r = 0.390, p = 0.007; cerebellum volume, r = - 0.393, p = 0.024) after adjustment for age. NfL levels were higher close to the expected age of onset in preclinical individuals with SCA2 (R2 = 0.43, p = 0.04).Discussion:Levels of serum NfL were correlated with disease intensity in individuals with SCA2, and were higher close to the estimated age of onset in preclinical SCA2. Therefore, NfL is a potential serum biomarker of disease severity in SCA2.Classification of Evidence:This study provides Class II evidence that elevated NfL levels are associated with disease severity in individuals with SCA2.
Background
Although many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients. Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population.
Methods
Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing (WES) and copy number variation (CNV) calling with ExomeDepth. Likely causal CNV predictions were validated by CNVseq.
Results
Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, of which four most common genes were SACS, SYNE1, ADCK3 and SETX, which accounted for 76.0% (19/25) of the positive cases. The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Clinical features of the patients carrying SACS, SYNE1 and ADCK3 mutations were summarized.
Conclusions
Our results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.
Spinocerebellar ataxia type 3 (SCA3) is caused by unstable expanded CAG repeats (expCAGs) in ATXN3. Factors associated with intergenerational instability (delta-expCAG) and genetic anticipation in SCA3 have never been reported in Chinese mainland. Here, we demonstrated that unstable transmissions occurred more often in sons than in daughters (91% vs 72%, Fisher's exact test, p = 0.012). The extended delta-expCAG of father-son transmissions was greater than that of mother-son transmissions (3.8 ± 2.3 repeats vs 1.6 ± 1.0 repeats, Mann-Whitney U, p = 0.001). Genetic anticipation was frequently observed between generations but not affected by the delta-expCAG.
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