Authors: Alessandra d’Azzo, Eda Machado, and Ida Annunziata

Published: April, 2015

Abstract:

Introduction: Sialidosis is a neurosomatic, lysosomal storage disease (LSD) caused by mutations in the NEU1 gene, encoding the lysosomal sialidase NEU1. Deficient enzyme activity results in impaired processing/degradation of sialo-glycoproteins, and accumulation of oversialylated metabolites. Sialidosis is considered an orphan disorder for which no therapy is currently available.

Areas covered: The review describes the clinical forms of sialidosis and the NEU1 mutations so far identified; NEU1 requirement to complex with the protective protein/cathepsin A for stability and activation; and the pathogenic effects of NEU1 deficiency. Studies of the molecular mechanisms of pathogenesis in animal models uncovered basic cellular pathways downstream of NEU1 and its substrates, which may be implicated in more common adult (neurodegenerative) diseases. The development of a Phase I/II clinical trial for patients with galactosialidosis may prove suitable for sialidosis patients with the attenuated form of the disease.

Expert opinion: Recently, there has been a renewed interest in the development of therapies for orphan LSDs, like sialidosis. Given the small number of potentially eligible patients, the way to treat sialidosis would be through the coordinated effort of clinical centers, which provide diagnosis and care for these patients, and the basic research labs that work towards understanding the disease pathogenesis.

Keywords: NEU1, sialidosis, mechanisms of pathogenesis, lysosomal storage disease, lysosomal exocytosis, chaperone-mediated therapy

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Authors: Eda R. Machado, Diantha van de Vlekkert, Heather S. Sheppard, Scott Perry, Susanna M. Downing, Jonathan Laxton, Richard Ashmun, David B. Finkelstein, Geoffrey A. Neale, Huimin Hu, Frank C. Harwood, Selene C. Koo, Gerard C. Grosveld, and Alessandra d’Azzo

Published: September, 2022

Abstract

Rhabdomyosarcoma, the most common pediatric sarcoma, has no effective treatment for the pleomorphic subtype. Still, what triggers transformation into this aggressive phenotype remains poorly understood. Here we used Ptch1+/−/ETV7TG/+/− mice with enhanced incidence of rhabdomyosarcoma to generate a model of pleomorphic rhabdomyosarcoma driven by haploinsufficiency of the lysosomal sialidase neuraminidase 1. These tumors share mostly features of embryonal and some of alveolar rhabdomyosarcoma. Mechanistically, we show that the transforming pathway is increased lysosomal exocytosis downstream of reduced neuraminidase 1, exemplified by the redistribution of the lysosomal associated membrane protein 1 at the plasma membrane of tumor and stromal cells. Here we exploit this unique feature for single cell analysis and define heterogeneous populations of exocytic, only partially differentiated cells that force tumors to pleomorphism and promote a fibrotic microenvironment. These data together with the identification of an adipogenic signature shared by human rhabdomyosarcoma, and likely fueling the tumor’s metabolism, make this model of pleomorphic rhabdomyosarcoma ideal for diagnostic and therapeutic studies.

Subject terms: Cancer models, Cancer genetics

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Authors: Felipe Vial, Patrick McGurrin, Sanaz Attaripour, Alesandra d'Azzo, Cynthia J. Tifft, Camilo Toro, and Mark Hallett

Published: June, 2022

Abstract

Objective: Sialidosis is an inborn error of metabolism. There is evidence that the myoclonic movements observed in this disorder have a cortical origin, but this mechanism does not fully explain the bilaterally synchronous myoclonus activity frequently observed in many patients. We present evidence of a subcortical basis for synchronous myoclonic phenomena.

Methods: Electromyographic investigations were undertaken in two molecularly and biochemically confirmed patients with sialidosis type-1.

Results: The EMG recordings showed clear episodes of bilaterally synchronous myoclonic activity in contralateral homologous muscles. We also observed a high muscular-muscular coherence with near-zero time-lag between these muscles.

Conclusion: The absence of coherence phase lag between the right-and-left homologous muscles during synchronous events indicates that a unilateral cortical source cannot fully explain the myoclonic activity. There must exist a subcortical mechanism for bilateral synchronization accounting for this phenomenon.

Significance: Understanding this mechanism may illuminate cortical-subcortical relationships in myoclonus.

Keywords: Sialidosis, Myoclonus

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Authors: Antonietta Coppola, Marta Ianniciello, Ebru N. Vanli-Yavuz, Settimio Rossi, Francesca Simonelli, Barbara Castellotti, Marcello Esposito, Stefano Tozza, Serena Troisi, Marta Bellofatto, Lorenzo Ugga, Salvatore Striano, Alessandra D’Amico, Betul Baykan, Pasquale Striano, and Leonilda Bilo

Published: August, 2020

Abstract: Background: Sialidosis is a rare autosomal recessive disease caused by NEU1 mutations, leading to neuraminidase deficiency and accumulation of sialic acid-containing oligosaccharides and glycopeptides into the tissues. Sialidosis is divided into two clinical entities, depending on residual enzyme activity, and can be distinguished according to age of onset, clinical features, and progression. Type 1 sialidosis is the milder, late-onset form, also known as non-dysmorphic sialidosis. It is commonly characterized by progressive myoclonus, ataxia, and a macular cherry-red spot. As a rare condition, the diagnosis is often only made after few years from onset, and the clinical management might prove difficult. Furthermore, the information in the literature on the long-term course is scarce. Case presentations: We describe a comprehensive clinical, neuroradiological, ophthalmological, and electrophysiological history of four unrelated patients affected by type 1 sialidosis. The long-term care and novel clinical and neuroradiological insights are discussed. Discussion and conclusions: We report the longest follow-up (up to 30 years) ever described in patients with type 1 sialidosis. During the course, we observed a high degree of motor and speech disability with preserved cognitive functions. Among the newest antiseizure medication, perampanel (PER) was proven to be effective in controlling myoclonus and tonic–clonic seizures, confirming it is a valid therapeutic option for these patients. Brain magnetic resonance imaging (MRI) disclosed new findings, including bilateral gliosis of cerebellar folia and of the occipital white matter. In addition, a newly reported variant (c.914G > A) is described.

Keywords: type-1-sialidosis, myoclonus, brain MRI, cherry-red spot, giant SEP, jerk-locked back averaging analysis

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Authors: Rosario Mosca, Diantha van de Vlekkert, Yvan Campos, Leigh E. Fremuth, Jaclyn Cadaoas, Vish Koppaka, Emil Kakkis, Cynthia Tifft, Camilo Toro, Simona Allievi, Cinzia Gellera, Laura Canafoglia, Gepke Visser, Ida Annunziata, and Alessandra d’Azzo

Published: March, 2020

Abstract: 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.

Keywords: sialidosis type I, NEU1, PPCA, dietary and pharmacological compounds, therapy

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Authors: Aiza Khan and Consolato Sergi

Published: April, 2018

Abstract: Sialidosis (MIM 256550) is a rare, autosomal recessive inherited disorder, caused by α-N-acetyl neuraminidase deficiency resulting from a mutation in the neuraminidase gene (NEU1), located on 6p21.33. This genetic alteration leads to abnormal intracellular accumulation as well as urinary excretion of sialyloligosaccharides. A definitive diagnosis is made after the identification of a mutation in the NEU1 gene. So far, 40 mutations of NEU1 have been reported. An association exists between the impact of the individual mutations and the severity of clinical presentation of sialidosis. According to the clinical symptoms, sialidosis has been divided into two subtypes with different ages of onset and severity, including sialidosis type I (normomorphic or mild form) and sialidosis type II (dysmorphic or severe form). Sialidosis II is further subdivided into (i) congenital; (ii) infantile; and (iii) juvenile. Despite being uncommon, sialidosis has enormous clinical relevance due to its debilitating character. A complete understanding of the underlying pathology remains a challenge, which in turn limits the development of effective therapeutic strategies. Furthermore, in the last few years, some atypical cases of sialidosis have been reported as well. We herein attempt to combine and discuss the underlying molecular biology, the clinical features, and the morphological patterns of sialidosis type I and II.

Keywords: sialidosis, neuraminidase, sialidosis I, sialidosis II, lysosomal storage disease, lysosomal exocytosis

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Authors: Juliana de Carvalho Neves, Vanessa Rodrigues Rizzato, Alan Fappi, Mariana Miranda Garcia, Gerson Chadi, Diantha van de Vlekkert, Alessandra d’Azzo, and Edmar Zanoteli

Published: May, 2015

Abstract: Neuraminidase-1 (NEU1) is the sialidase responsible for the catabolism of sialoglycoconjugates in lysosomes. Congenital NEU1 deficiency causes sialidosis, a severe lysosomal storage disease associated with a broad spectrum of clinical manifestations, which also include skeletal deformities, skeletal muscle hypotonia and weakness. Neu1−/− mice, a model of sialidosis, develop an atypical form of muscle degeneration caused by progressive expansion of the connective tissue that infiltrates the muscle bed, leading to fiber degeneration and atrophy. Here we investigated the role of Neu1 in the myogenic process that ensues during muscle regeneration after cardiotoxin-induced injury of limb muscles. A comparative analysis of cardiotoxin-treated muscles from Neu1−/− mice and Neu1+/+ mice showed increased inflammatory and proliferative responses in the absence of Neu1 during the early stages of muscle regeneration. This was accompanied by significant and sequential upregulation of Pax7, MyoD, and myogenin mRNAs. The levels of both MyoD and myogenin proteins decreased during the late stages of regeneration, which most likely reflected an increased rate of degradation of the myogenic factors in the Neu1−/− muscle. We also observed a delay in muscle cell differentiation, which was characterized by prolonged expression of embryonic myosin heavy chain, as well as reduced myofiber cross-sectional area. At the end of the regenerative process, collagen type III deposition was increased compared to wild-type muscles and internal controls, indicating the initiation of fibrosis. Overall, these results point to a role of Neu1 throughout muscle regeneration.

Keywords: NEU1, sialidosis, skeletal muscle regeneration, cell proliferation, muscle maturation, fibrosis

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