Pathogenesis, emerging therapeutic targets and treatment in sialidosis

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.

Child Neurology: Type 1 sialidosis due to a novel mutation in NEU1 gene

“…7 To date, around 50 mutations in the NEU1 gene have been reported in patients with sialidosis. 4,8,9 To our knowledge, the c.629C>T mutation of NEU1 found in our patient has not been reported. This missense alteration causes replacement of the amino acid proline by leucine at codon 210.…”

“…4 Sialidase is a part of lysosomal multienzyme complex and acts in removing terminal sialic acid molecules from oligosaccharides and glycoproteins. Impaired sialidase activity therefore leads to storage of sialic acid-rich macromolecules in multiple organs including liver, kidneys, brain, skin, conjunctiva, peripheral leukocytes, and bone marrow cells.…”

“…Clinical phenotype correlates closely with the type of NEU1 mutations and the levels of residual enzyme activity. [4][5][6] Type 2 sialidosis is the severe form that has 3 subtypes: congenital with onset in utero, infantile with onset between birth and 12 months, and juvenile with onset after 2 years of age. Babies with congenital form of the disease develop hydrops fetalis, neonatal ascites, inguinal hernias, and hepatosplenomegaly.…”

“…Life expectancy varies based on genotype and phenotypic severity; however, most patients become wheelchair-bound within few years due to severe myoclonus causing motor deterioration. [4][5][6] Neuropathologic features include vacuolations with neuronal intracytoplasmic lipofuscin-like pigment storage seen in the neocortex, basal ganglia, thalamus, brainstem, and spinal cord. No abnormalities are seen on brain MRI in early stages of the disease whereas atrophy of the cerebral cortex, pons, and cerebellum may be seen during progression.…”

“…Confirmation is by demonstrating enzyme deficiency in cultured fibroblasts or genetic testing. 4,5 Current pharmacologic management involves treating the myoclonic epilepsy. Antiepileptics that have been used include valproic acid, levetiracetam, phenobarbital, zonisamide, and benzodiazepines.…”