• NEU1
• ataxia
• cherry-red spots
• myoclonus
• neuraminidase 1
• sialidosis

• Humans
• Mucolipidoses/genetics
• Mucolipidoses/pathology
• Neuraminidase/genetics
• Turkey
• Male
• Female
• Mutation
• Pedigree
• Child
• Prognosis
• Adolescent
• Child, Preschool

• Alpha-N-acetyl neuraminidase
• Cherry-red spot
• Muscle spasm
• NEU1
• Sialidosis

• Humans
• Female
• Mucolipidoses/genetics
• Mucolipidoses/physiopathology
• Male
• Child
• Evoked Potentials, Visual/physiology
• Neuraminidase

• No. 7234365 Beijing Natural Science Foundation
• Beijing Natural Science Foundation

• Genotype
• NEU1
• Phenotype
• Sialidosis
• Structure

• 2022YFC2703600 National Key Research and Development Program of China
• 82301385 National Natural Science Foundation of China

• Diagnostic tests/Investigation
• Genetics
• Imaging
• Macula
• Retina

• Adolescent
• Adult
• Child
• Female
• Fluorescein Angiography/methods
• Fundus Oculi
• Humans
• Macula Lutea/pathology
• Male
• Mucolipidoses/complications
• Mucolipidoses/diagnosis
• Multimodal Imaging
• Retinal Diseases/diagnosis
• Retinal Diseases/etiology
• Tomography, Optical Coherence/methods
• Visual Acuity
• Young Adult

• R01 GM104981 NIGMS NIH HHS

• NEU1
• induced pluripotent stem cell
• lysosomal storage disease
• neural cell model
• sialidosis

• Astrocytes/metabolism
• Astrocytes/pathology
• Autophagy
• Cell Differentiation
• Humans
• Induced Pluripotent Stem Cells/metabolism
• Induced Pluripotent Stem Cells/pathology
• Lysosomes
• Mucolipidoses/genetics
• Mucolipidoses/metabolism
• Mucolipidoses/pathology
• Mutation
• Neural Stem Cells/metabolism
• Neural Stem Cells/pathology
• Neuraminidase/genetics
• Neuraminidase/metabolism
• Oligodendroglia/metabolism
• Oligodendroglia/pathology
• Phenotype
• Teratoma/genetics
• Teratoma/metabolism
• Teratoma/pathology

Type 1 sialidosis, also known as cherry-red spot-myoclonus syndrome, is a rare autosomal recessive lysosomal storage disorder presenting in the second decade of life. The most common symptoms are myoclonus, ataxia and seizure. It is rarely encountered in the Chinese mainland.

A 22-year-old male presented with complaints of progressive myoclonus, ataxia and slurred speech, without visual symptoms; the presenting symptoms began at the age of 15-year-old. Whole exome sequencing revealed two pathogenic heterozygous missense variants [c.239C>T (p.P80L) and c.544A>G (p.S182G) in the neuraminidase 1 (NEU1) gene], both of which have been identified previously in Asian patients with type 1 sialidosis. All three patients identified in Mainland China come from three unrelated families, but all three show the NEU1 mutations p.S182G and p.P80L pathogenic variants. Increasing sialidase activity through chaperones is a promising therapeutic target in sialidosis.

Through retrospective analysis and summarizing the clinical and genetic characteristics of type 1 sialidosis, we hope to raise awareness of lysosomal storage disorders among clinicians and minimize the delay in diagnosis.

• Sialidosis
• Myoclonus
• Ataxia
• Neuraminidase 1
• Case report
• Mucolipidoses

• CLN3 disease
• ImageStream
• flow cytometry
• lymphocyte vacuolization
• lysosomal membrane‐associated protein‐1 (LAMP‐1)
• neuronal ceroid lipofuscinosis (NCL)

Type I sialidosis (ST‐1) is a rare autosomal recessive inherited disorder. To date, there has been no study on ST‐1 patients in mainland China.

We reported in detail the cases of five Chinese ST‐1 patients from two centers, and summarized all worldwide cases. Then, we compared the differences between Chinese and foreign patients.

A total of 77 genetically confirmed ST‐1 patients were identified: 12 from mainland China, 23 from Taiwan, 10 from other Asian regions, and 32 from European and American regions. The mean age of onset was 16.0 ± 6.7 years; the most common symptoms were myoclonus seizures (96.0%), followed by ataxia (94.3%), and blurred vision (67.2%). Compared to other groups, the onset age of patients from mainland China was much younger (10.8 ± 2.7 years). The incidence of visual impairment was lower in patients from other Asian regions than in patients from mainland China and Taiwan (28.6% vs. 81.8%–100%). Cherry‐red spots were less frequent in the Taiwanese patients than in patients from other regions (27.3% vs. 55.2%–90.0%). Furthermore, 48 different mutation types were identified. Chinese mainland and Taiwanese patients were more likely to carry the c.544A > G mutation (75% and 100%, respectively) than the patients from other regions (only 0%–10.0%). Approximately 50% of Chinese mainland patients carried the c.239C > T mutation, a much higher proportion than that found in the other populations. In addition, although the brain MRI of most patients was normal, ¹⁸F‐FDG‐PET analysis could reveal cerebellar and occipital lobe hypometabolism.

ST‐1 patients in different regions are likely to have different mutation types; environmental factors may influence clinical manifestations. Larger studies enrolling more patients are required.

Sialidosis type 1 is a rare inherited disorder with a high disability. No genetically confirmed mainland Chinese patient with sialidosis type 1 has been reported. This study evaluated the phenotypes and genotypes of mainland Chinese patients with sialidosis type 1.

It was a retrospective case series study. Four unrelated patients were enrolled. Comprehensive clinical evaluations and molecular genetic analysis of the NEU1 gene were performed.

Three out of four patients presented progressive myoclonus epilepsy. The best‐corrected visual acuity ranged from 20/2000 to 20/25. Punctate cataracts were found in all of the patients. Distinct macular cherry red spots were observed in three patients by fundoscopy, and a relatively normal fundus was revealed in one patient. Optical coherence tomography (OCT) showed increased reflectivity of the nerve fiber and ganglion cell layers, and fundus autofluorescence (FAF) revealed hyperautofluorescent areas surrounding the fovea in all of the patients. Only superficial retinal vessels can be observed using OCT angiography; the deeper capillary plexus could not be observed. Visual evoked potential revealed varying degrees of decreased amplitude and/or prolonged latency of P100 or P2 waves. The most frequent sequence variant identified was c.544A>G (p.S182G) (NM_000434.3).

Our study first described the ophthalmic and neurologic characteristics of a small cohort of unrelated mainland Chinese patients with sialidosis type 1. We found that c.544A>G (p. S182G) might be a hotspot variant in Chinese patients. The accumulation of metabolic products in the nerve fiber and ganglion cell layers is a characteristic ocular finding that could be sensitively detected by OCT and FAF imaging.

• FAF
• OCT
• OCTA
• macular cherry red spot
• sialidosis type 1

Congenital deficiency of the lysosomal sialidase neuraminidase 1 (NEU1) causes the lysosomal storage disease, sialidosis, characterized by impaired processing/degradation of sialo-glycoproteins and sialo-oligosaccharides, and accumulation of sialylated metabolites in tissues and body fluids. Sialidosis is considered an ultra-rare clinical condition and falls into the category of the so-called orphan diseases, for which no therapy is currently available. In this study we aimed to identify potential therapeutic modalities, targeting primarily patients affected by type I sialidosis, the attenuated form of the disease. We tested the beneficial effects of a recombinant protective protein/cathepsin A (PPCA), the natural chaperone of NEU1, as well as pharmacological and dietary compounds on the residual activity of mutant NEU1 in a cohort of patients’ primary fibroblasts. We observed a small, but consistent increase in NEU1 activity, following administration of all therapeutic agents in most of the fibroblasts tested. Interestingly, dietary supplementation of betaine, a natural amino acid derivative, in mouse models with residual NEU1 activity mimicking type I sialidosis, increased the levels of mutant NEU1 and resolved the oligosacchariduria. Overall these findings suggest that carefully balanced, unconventional dietary compounds in combination with conventional therapeutic approaches may prove to be beneficial for the treatment of sialidosis type I.

• NEU1
• PPCA
• dietary and pharmacological compounds
• sialidosis type I
• therapy

• GM104981 NIH HHS
• NA Assisi Foundation of Memphis
• NA American Lebanese Syrian Associated Charities
• NA Ultragenyx Pharmaceuticals

• Asp-Box regions
• NEU1 gene mutations
• alpha-N-acetyl neuraminidase 1 (NEU1)
• cherry red spots
• myoclonus
• sialidosis

• Adolescent
• Adult
• Ataxia/diagnosis
• Child
• Diagnosis, Differential
• Female
• Humans
• Lysosomes/pathology
• Mucolipidoses/diagnosis
• Mucolipidoses/genetics
• Mutation, Missense
• Myoclonus/diagnosis
• Neuraminidase/genetics
• Phenotype
• Young Adult

Sialidosis, an autosomal recessive disorder, is characterized by progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. It occurs as a result of biallelic mutations in the NEU1 gene. Sialidosis is traditionally classified as a milder, late-onset type I and a severe early-onset type II disease. The presence of a cherry-red spot is a well-established ophthalmological clue to the disorder. We present a clinical-radiological report of seven unrelated patients with molecularly confirmed sialidosis type II. To the best of our knowledge, This is the largest reported series of patients with Sialidosis type II. A novel, previously unreported ophthalmic phenotype of bulls-eye maculopathy, is described. All seven phenotypically heterogeneous patients had the same pathogenic variant (c.679G > A; p.Gly227Arg) at a homozygous level in the NEU1 gene. We propose that this is a common mutation in north Indians for this rare disorder. We also observed an overlap of symptoms and a continuum of phenotypes in type I and II Sialidosis.

• Bull's eye maculopathy
• Common mutation
• NEU1
• North India
• Polypheny
• Sialidosis type II

• Lysosomal storage disease
• NEU1 gene
• Next-generation sequencing
• Sialidosis

• Adult
• Female
• Humans
• Mucolipidoses/genetics
• Mutation, Missense
• Neuraminidase/genetics

• Ataxia
• Evoked potential
• Myoclonus
• NEU1
• Sialidosis

• Ataxia
• Myoclonus
• NEU1
• Neurodeaminiase
• Sialidosis
• WES, Whole exome sequencing

Lysosomal storage diseases (LSD) often manifest with cherry red macular spots. Diagnosis is based on clinical features and specific biochemical and enzymatic patterns. In uncertain cases, genetic testing with next generation sequencing can establish a diagnosis, especially in milder or atypical phenotypes. We report on the diagnostic work-up in a boy with sialidosis type I, presenting initially with marked cherry red macular spots but non-specific urinary oligosaccharide patterns and unusually mild excretion of bound sialic acid.

Biochemical, enzymatic and genetic tests were performed in the patient. The clinical and electrophysiological data was reviewed and a genotype-phenotype analysis was performed. In addition a systematic literature review was carried out.

Cherry red macular spots were first noted at 6 years of age after routine screening myopia. Physical examination, psychometric testing, laboratory investigations as well as cerebral MRI were unremarkable at 9 years of age. So far no clinical myoclonic seizures occurred, but EEG displays generalized epileptic discharges and visual evoked potentials are prolonged bilaterally. Urine thin layer chromatography showed an oligosaccharide pattern compatible with different LSD including sialidosis, galactosialidosis, GM1 gangliosidosis or mucopolysaccharidosis type IV B. Urinary bound sialic acid excretion was mildly elevated in spontaneous and 24 h urine samples. In cultured fibroblasts, α-sialidase activity was markedly decreased to < 1%; however, bound and free sialic acid were within normal range. Diagnosis was eventually established by multigene panel next generation sequencing of genes associated to LSD, identifying two novel, compound heterozygous variants in NEU1 gene (c.699C > A, p.S233R in exon 4 and c.803A > G; p.Y268C in Exon 5 in NEU1 transcript NM_000434.3), leading to amino acid changes predicted to impair protein function.

Sialidosis should be suspected in patients with cherry red macular spots, even with non-significant urinary sialic acid excretion. Multigene panel next generation sequencing can establish a definite diagnosis, allowing for counseling of the patient and family.

• DNA, deoxyribonucleic acid
• EEG, electroencephalography
• Lysosomal storage disease
• Multigene panel next generation sequencing
• NEU1 gene
• Sialidosis
• c.699C > A (p.S233R)
• c.803A > G (p.Y268C)