Sialidosis

Raphael Schiffmann MD (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released February 3, 1994; last updated December 19, 2016; expires December 19, 2019

This article includes discussion of sialidosis, cherry-red spot myoclonus syndrome, glycoprotein neuraminidase deficiency, lipomucopolysaccharidosis, ML I, mucolipidosis I, NEU deficiency, NEU1 deficiency, NEUG deficiency, neuraminidase 1 deficiency, sialidase deficiency, sialidosis type1, and sialidosis type 2, sialidosis type I, and sialidosis type II. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Sialidosis is an autosomal recessive lysosomal storage disorder caused by deficiency of neuraminidase 1 due to NEU1 mutations. Sialidosis type I is characterized by the development of ocular cherry-red spots and generalized myoclonus in the second or third decade of life. Seizures, hyperreflexia, ataxia, and progressive atrophy on brain MRI may also occur. Type II sialidosis is more severe than type I and is distinguished by the early onset of a progressive, rather severe, mucopolysaccharidosis-like phenotype with visceromegaly, dysostosis multiplex, and intellectual disability. In severe cases, hydrops fetalis may occur. Therapy based on over-expressing the neuraminidase chaperone, protective protein/cathepsin A (PPCA), may be useful in the future in this disease.

Key points

 

• Sialidosis is a disorder of sialic acid metabolism.

 

• It is often associated with myoclonic epilepsy in juveniles or young adults.

 

• Eye and skeletal abnormalities may be helpful for the diagnosis.

 

• Macular cherry-red spots may occur in otherwise asymptomatic patients.

Historical note and terminology

The term "sialidosis" is used here to describe those patients with a disorder resulting from an inherited, isolated deficiency of neuraminidase 1 (sialidase) (Lowden and O'Brien 1979; O'Brien 1982; Beaudet and Thomas 1989; Cantz and Ulrich-Bott 1990). Because the first patients shown to suffer from this enzyme abnormality had originally been included in a group of patients given the designation "mucolipidosis" (Spranger and Wiedermann 1970), this disorder is also sometimes referred to as mucolipidosis I (Spranger et al 1977). The enzyme defect was first demonstrated in this group of patients in 1977 (Cantz et al 1977; Spranger et al 1977). Within a year, several investigators independently described an adult group of patients with deficiencies of neuraminidase 1 activity (Durand et al 1977; O'Brien 1977; Rapin et al 1978; Thomas et al 1978). This form of the disorder, originally labeled the cherry-red spot-myoclonus syndrome, is now referred to as sialidosis type I.

Sialidosis (mucolipidosis I) is not to be confused with mucolipidosis II (I-cell disease) or mucolipidosis III (pseudo-Hurler polydystrophy). Although patients with these latter disorders are also characterized by neuraminidase deficiencies, the defect is neither a primary nor an isolated abnormality. Rather, the neuraminidase deficiencies in mucolipidosis II and III are the secondary result of defective post-translational modification involving many lysosomal enzymes (Nolan and Sly 1989). Mucolipidosis IV, while sharing the same name, is also a distinct and genetically unrelated disorder. It is caused by mutations in MCOLN1 that codes for a protein called mucolipin 1, thought to be a cationic ion channel (Schiffmann et al 2015).

The classification of sialidosis is also complicated by the existence of a combined neuraminidase and beta-galactosidase deficiency, generally referred to as galactosialidosis (O'Brien 1989). A variety of studies, such as somatic cell hybridization and biochemical and genetic mapping, have clearly demonstrated that the sialidosis and galactosialidosis result from mutations of different genes and are, thus, 2 distinct disorders.

Sialidosis must also be distinguished from sialuria, the term given to a group of patients who excrete excessive amounts of free sialic acid due to the defective feedback control of UDP-GlcNAc 2-epimerase (Thomas et al 1985; Seppala et al 1999). Finally, sialidosis patients should not be confused with those patients suffering from free sialic storage disease or Salla disease, both of which are the result of the defective transport of sialic acid across lysosomal membranes (Aula et al 2002).

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