Pitfalls in Diagnosing Neuraminidase Deficiency: Psychosomatics and Normal Sialic Acid Excretion

Schene, Imre F.; Ayuso, Viera Kalinina; Velden, Monique de Sain-van der; Gassen, Koen van; Cuppen, Inge; Hasselt, Peter M. van; Visser, Gepke

doi:10.1007/8904_2015_472

Cited by 17 publications

(11 citation statements)

References 12 publications

(17 reference statements)

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“…The S182G variant has been reported previously in the homozygous state in an individual with sialidosis type 1 [4] . The G227R variant has also been reported previously in homozygous and compound heterozygous state in individuals with NEU1 -related disorders [10] , [11] , [12] . These variants are non-conservative amino acid substitution, which are likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.…”

Section: Resultssupporting

confidence: 60%

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Type 1 sialidosis presenting with ataxia, seizures and myoclonus with no visual involvement

Mohammad¹,

Bruno²,

Hines³

et al. 2018

Molecular Genetics and Metabolism Reports

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Sialidosis is an autosomal recessive lysosomal storage disease caused by pathogenic variants in NEU1 which encodes lysosomal sialidase (neuraminidase 1). Lysosomal neuraminidase catalyzes the removal of terminal sialic acid molecules from glycolipids, glycoproteins and oligosaccharides. Sialidosis is classified into two types, based on phenotype and age of onset. Patients with the milder type 1 typically present late, usually in the second or third decade, with myoclonus, ataxia and visual defects. Type 2 is more severe and presents earlier with coarse facial features, developmental delay, hepatosplenomegaly and dysostosis multiplex. Presentation and severity of the disease are related to whether lysosomal sialidase is inactive or there is some residual activity. Diagnosis is suspected based on clinical features and increased urinary bound sialic acid excretion and confirmed by genetic testing showing pathogenic variants in NEU1. We report a patient with type 1 sialidosis who presented mainly with ataxia and both generalized and myoclonic seizures but no visual involvement. Whole exome sequencing of the proband detected compound heterozygous likely pathogenic variants (S182G and G227R) in NEU1.

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Section: Resultssupporting

confidence: 60%

“…We did not perform a urinary sialic acid test on our patient due to the ambiguity of testing, since having a negative urinary sialic acid test does not rule out sialidase deficiency [12] , [15] . His molecular and phenotypic data were consistent with sialidosis.…”

Section: Discussionmentioning

confidence: 99%

Type 1 sialidosis presenting with ataxia, seizures and myoclonus with no visual involvement

Mohammad¹,

Bruno²,

Hines³

et al. 2018

Molecular Genetics and Metabolism Reports

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“…Diagnosis resulted from the detection of NEU1 mutation through genome-wide screening (Canafoglia et al, 2014). Our observation, together with a recent similar report (Schene et al, 2015), points towards the possibility that mild and late forms present with 'cortical myoclonus' and are possibly misdiagnosed. Most of the patients, with either sialidosis type I or II, become wheelchair-bound within a few years due to severe motor impairment, mainly resulting from severe myoclonus.…”

Section: Clinical Presentationsupporting

confidence: 65%

“…Diagnosis resulted from the detection of NEU1 mutation through genome‐wide screening (Canafoglia et al ., ). Our observation, together with a recent similar report (Schene et al ., ), points towards the possibility that mild and late forms present with ‘cortical myoclonus’ and are possibly misdiagnosed.…”

Section: Clinical Presentationmentioning

confidence: 97%

Sialidoses

Franceschetti¹,

Canafoglia²

2016

Epileptic Disorders

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Sialidoses are autosomal recessive disorders caused by NEU1 gene mutations and are classified on the basis of their phenotype and onset age. Sialidosis type II, with infantile onset, has a more severe phenotype characterized by coarse facial features, hepatomegaly, dysostosis multiplex, and developmental delay while patients with the late and milder type, known as “cherry red spot‐myoclonus syndrome” develop myoclonic epilepsy, visual impairment and ataxia in the second or third decade of life. The diagnosis is usually suggested by increased urinary bound sialic acid excretion. We recently described genetically diagnosed patients with a specially mild phenotype, no retinal abnormalities and normal urinary sialic acid. This observation suggests that genetic analysis or the demonstration of the neuraminidase enzyme deficiency in cultured fibroblasts are needed to detect and diagnose mildest phenotypes.

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“…A list of the NEU1 mutations identified in these patients and their position in the primary structure of the protein are given in Figure 1A,B. For six of the patients, the mutations have been reported earlier [8,[16][17][18][19]. The remaining six patients, not described in the literature, carry novel All patients' fibroblasts expressed different levels of NEU1 mRNA, as determined by quantitative real-time PCR analysis, some even higher than wild-type (WT) levels ( Figure 1C).…”

Section: Characterization Of Fibroblasts From Type I Sialidosis Patientsmentioning

confidence: 97%

Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I

Mosca

Vlekkert

Campos

et al. 2020

JCM

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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.

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Pitfalls in Diagnosing Neuraminidase Deficiency: Psychosomatics and Normal Sialic Acid Excretion

Abstract: Neuraminidase deficiency (mucolipidosis

Cited by 17 publications

References 12 publications

Type 1 sialidosis presenting with ataxia, seizures and myoclonus with no visual involvement

Type 1 sialidosis presenting with ataxia, seizures and myoclonus with no visual involvement

Sialidoses

Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I

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