The investigation of genetic and clinical features in Chinese patients with juvenile amyotrophic lateral sclerosis

Abstract

Juvenile amyotrophic lateral sclerosis (JALS) occurs at an age of onset below 25 years with a heterogeneous disease onset location, variable progression and survival time. To investigate whether an ALS gene profile could resolve any aspects of clinical symptom heterogeneity, we have used targeted sequencing technology in a cohort of 12 JALS patients of Chinese descent. We detected 5 likely pathogenic mutations, 2 in familial probands and 3 in sporadic patients. One was a known TARDBP mutation (p.G348V) and 4 were FUS frameshift mutations including a known p.Gln519Ilefs*9 mutation and 3 novel mutations, p.Gly515Valfs*14, p.Gly486Profs*30, and p.Arg498Alafs*32. Of the 4 FUS mutations, 2 were able to be confirmed as de novo mutations. The TARDBP mutation carrier showed a classic ALS phenotype. All patients with FUS mutations experienced limb weakness at an early age and developed bulbar symptoms during the disease course. FUS mutations have previously been associated with increased JALS disease progression, however, we found a large range 12 to 84 months in disease survival (mean 58.2 months). Our results justify future screening for variants in FUS as it remains the most frequent genetic determinant of early onset, JALS (found in 30% of our patients).

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

“…In Chinese sporadic cases, mutations in FUS (1.3%) are more common than those in Caucasians (0.3%) (Supplementary Table S1) (Zou et al, 2017). In several studies focusing on juvenile ALS (jALS) cases in China, mutations in FUS were the most frequent in this rare group with the age of onset younger than 25 years old, which is consistent with Caucasians (Hübers et al, 2015; Liu et al, 2017b; Zou et al, 2013a, 2016). The early age of onset in Chinese ALS may be partially due to the relatively higher frequency of FUS mutations in familial and sporadic cases.…”

“…Unfortunately, mutations in above-mentioned genes are quite rare in Chinese population, suggesting genes may not be informative of the genetics in Chinese ALS patients (Chen et al, 2013; Li et al, 2016; Lin et al, 2015; Pan et al, 2017; Shen et al, 2017; Shu et al, 2016; Soong et al, 2014; Tsai et al, 2016, 2017; Xu et al, 2016; Zhou et al, 2017; Zou et al, 2013c). Targeted next-generation sequencing (NGS), a cost-effective approach for variant screening in known ALS genes, has been applied primarily in fALS and jALS (Liu et al, 2014b, 2017b). In addition, based on the data from targeted NGS, the cooccurrence of two or more variants of known ALS genes detected in one patient has been reported in 25% of fALS and 3.0% of sALS, respectively (Liu et al, 2016b).…”

A novel SETX gene mutation associated with Juvenile amyotrophic lateral sclerosis

“…In Chinese Han families with JALS, FUS mutations were reported to be the most common genetic determinant with an aggressive phenotype (Liu et al., 2017), especially the de novo ones (Zou et al., 2013). Mutations in the SETX gene are associated with a rare and autosomal dominant form of JALS, also known as ALS4, which is characterized by motor neuron dysfunction of early onset, slow progression, acute muscle weakness and pyramidal tract signs, and the absence of bulbar and sensory abnormalities (Orban et al., 2007).…”

“…Most of JALS cases were inherited in an autosomal recessive pattern. Mutations in senataxin (SETX) gene were described as a rare underlying cause of autosomal dominant form of juvenile‐onset FALS (Liu et al., 2017). According to the Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/index.php), only 17 SETX mutations have been yet reported to associate with ALS.…”

Genetic and clinical features of Chinese patients with mitochondrial ataxia identified by targeted next‐generation sequencing

“…For those subjects without mutations in hereditary ataxia genes, mtDNA and nDNA genes were screened with a panel covering mitochondrial 16 569 base pairs (NC_012920.1) and 56 nuclear genes involved in mitochondrial disorders (Table S2). The targeted NGS and data analysis were performed using our previously reported protocol . Sanger sequencing was used to validate the variants that passed the filtering criteria in the patients and their family members.…”