**5. Sialidosis**

Sialidosis (MIM#256550) is a LSD caused by the inherited deficiency of the lysosomal enzyme alpha-N-acetyl-neuraminidase-1 (NEU1), which cleaves the terminal sialic acid residues of several oliogosaccharides and polypeptides.

Therefore, the deficiency of NEU1 leads to the accumulation of sialic acid (Nacetylneuraminic acid) covalently linked to oligosaccharides and/or glycoproteins. This aspect distinguishes sialidoses from sialurias, in which the neuraminidase activity is normal or elevated with a storage and excretion of 'free' sialic acid, rather than 'bound' forms.

#### **5.1 Clinical aspects**

A systematic classification of Sialidosis has been provided by Lowden and O'Brien in 1979, who divided them in two main clinical variants: Type I, the milder form of the disease, which lacks the physical changes (normosomatic) and Type II, a more severe form with an earlier onset, which can be subdivided in 2 different phenotypes: congenital/neonatal and juvenile forms.

Patients affected with type I sialidosis, (normomorphic or 'cherry-red-spot, myoclonus syndrome'), generally manifest first clinical signs during school-age period or early adulthood. Progressive reduction of visual acuity, red-green and night blindness, bilateral cherry-red spots, punctate corneal opacity and nistagmus, are prominent symptoms. Ocular involvement is accompanied or followed by the appearance of motor impairment, with walking difficulties and myoclonus. Same cases may present seizures. In contrast with type II forms, these patients generally do not present dysmorphisms or bone dysplasia and they have a normal intelligence. Survival is usually long.

Type II congenital sialidosis may manifest in utero with foetal hydrops or foetal ascites while the neonatal form is characterised by diffused edema, hepatosplenomegaly, ascites and Hurler's like clinical signs: facial dysmorphisms, umbilical and inguinal hernias, short trunk with a prominent sternum, kyphosis, and dysostosis multiplex (Froissart et al., 2005). Severe dysmrphisms (coarse facies, pectus carinatum, short trunk, exaggerated toracic kyphosis, and wadding gait) as well as growth delay characterize also infantile phenotypes, cherry-red spot, corneal opacity, hearing loss, progressive neurodegeneration and cognitive deterioration with myoclonic seizures. Skeletal imaging shows dysostosis multiplex with vertebral abnormalities and generalized osteoporosis. Renal involvement, nephrosialidosis, may be present in some patients with proteinuria evolving to nephrotic syndrome (Okada et al., 1983).

Juvenile onset is charactrized by less pronounced dysmorphic signs with muscular hypotonia and hypotrophy, ataxia, and myoclonic seizures. Cherry-red spots and corneal opacities are constantly present, as well as hearing loss. Pyramidal syndrome with cerebellar anomalies and peripheral neuropaty have been described. Mental retardation is costant. Survival rarely exceed the second, third decade of life (Winter et al., 1980; Caciotti et al., 2009; Canafoglia et al., 2011).
