Progressive myoclonic ataxia as an initial symptom of typical type I sialidosis with NEU1 mutation

Abstract

Objective: Expand genetic screening for atypical Type I sialidosis (ST-1) could address its underdiagnosed in both progressive myoclonic ataxia (PMA) and ataxia patients. To evaluate the potential founder effect of mutation in the population.

Methods: We enrolled 231 patients with PMA or ataxia from the First Affiliated Hospital of Fujian Medical University. Through Whole Exome Sequencing and Sanger sequencing, we identified the causative gene in patients. Haplotype analysis was employed to explore a potential founder effect of the NEU1 c.544A>G mutation.

Results: A total of 31 patients from 23 unrelated families were genetically diagnosed with ST-1. A significant 80.6% of these patients were homozygous for the c.544A>G mutation. We discovered six different NEU1 variants, including two novel mutations: c.951_968del and c.517T>G. The mean age of onset was 18.0 ± 7.1 years. The clinical spectrum of ST-1 featured ataxia and myoclonus as the most common initial symptoms. Over 40% suffered from controlled generalized tonic-clonic seizures. Mobility and independence varied greatly across the cohort. Cherry-red spots were rare, occurring in just 9.5% (2/21) of patients. Brain MRIs were typically unremarkable, except for two patients with unusual findings. EEGs showed diffuse paroxysmal activity in 17 patients. The c.544A>G mutation in NEU1 is a founder variant in Fujian, with a unique haplotype prevalent in East Asians.

Interpretation: ST-1 should be suspected in patients with PMA or ataxia in Southeast China, even without macular cherry-red spots and seizures, and the premier test could be a variant screening of the founder variant NEU1 c.544A>G.

Figure 1

Family pedigree and clinical profiles of patients with type I sialidosis. (A) Pedigrees of 23 ST‐1 families with NEU1 mutations. Men are represented by squares, women by circles. Filled, empty and slashed symbols indicate affected individuals, unaffected individuals, and deceased individuals, respectively. Double lines indicate parental consanguinity. ‐, reference allele. The red dots indicate genotyped individuals. (B) Distribution of initial symptoms in ST1 patients. (C) Age of onset distribution for patients with different initial symptoms. (D) Relationship between mobility states and disease duration.

Figure 2

Auxiliary examination results of patients. (A) Color fundus photographs of the patient Fam F‐3 showed bilateral cherry‐red spots in the macular. (B) Optical coherence tomography of patient Fam B‐6 and Fam L‐3 showed thinning of the retinal nerve fiber layer. (C) Brain MRI of the patient Fam M‐4 exhibited several linear dilated veins in the left cerebellar hemisphere and pontic arm. The diffuse weighted imaging (DWI) sequence revealed flow shadows. On T2‐weighted image (T2WI), the lesion was illegible. Brain MRI of Patient Fam P‐4 showed several spot‐like T2WI hyperintensities in the bilateral frontal and parietal lobes, as well as patchy T2WI hyperintensities and T1‐weighted image hypointensities in the left temporal lobe. (D) EEG of the patient Fam P‐4 showed generalized polyspike and polyspike‐slow waves.

Figure 3

Molecular and biochemical characteristics of sialidosis patients. (A) Distribution of mutations within the NEU1 gene and primary structure of neuraminidase. Two novel mutation (c.951_968delGGTAGCTGCAGGAGCTGT/p.318‐323delVAAGAV and c.517T>G/p.W173G) (labeled in red) and two previous reported mutations (c.544A>G/p.S182G and c.403G⟩A/p.D135N) (labeled in black) were identified. (B) Western blot analysis showed a significant decrease in protein expression for all Neu1 mutants compared to WT. (C) Quantification of Neu1 protein levels confirmed the reduction in expression for the mutant variants. (D) Neuraminidase activity assay demonstrated significantly reduced enzyme activity in cells expressing Neu1 mutants compared to WT. (E) Elevated total sialic acid levels were observed in the urine of two ST‐1 positive patients compared to healthy controls (HCs). (F) Free sialic acid levels were mildly elevated in patients with compound heterozygous mutations (c.544A>G, p.S182G and c.1118T>C, p.L373P).

Figure 4

Identification of the founder haplotype. Haplotype analysis of 14 SNP markers flanking the NEU1 gene in 18 pedigrees harboring the NEU1 c.544A>G (chr6:31829036) homozygous mutation (in orange) showed the 0.97 Mb core haplotype between rs9394023 and rs1048709 (except for Fam‐I‐4). The linked haplotype is labeled with blue and genotypes that could be fully phased are shown in red. Fourteen SNPs are showed in forward orientation. Allele frequencies of SNPs in East Asian population from gnomAD V2.1.1 (include only Genomes) were shown. Genomic locations are from the Genome Reference Consortium Human Build 37.