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Sialidosis type 2
Sialidosis type 2 (ST-2) is a rare lysosomal storage disease, and the severe, early onset form of sialidosis (see this term) characterized by a progressively severe mucopolysaccharidosis-like phenotype (coarse facies, dysostosis multiplex, hepatosplenomegaly), macular cherry-red spots as well as psychomotor and developmental delay. ST-2 displays a broad spectrum of clinical severity with antenatal/congenital, infantile and juvenile presentations.
ORPHA:87876Classification level: Disorder
The prevalence of ST-2 is unknown. The prevalence of sialidosis (types 1 and 2 combined) has been estimated at approximately 1/5,000,000-1/1,500,000 live births.
ST-2 has a wide range of clinical manifestations and is usually divided into congenital/antenatal, infantile and juvenile forms. The congenital/antenatal form is characterized by non-immune hydrops fetalis, or ascites, presenting in utero or at birth and by the development of a mucopolysaccharidosis (see this term)-like phenotype including coarse facial features, dysostosis multiplex, hepatosplenomegaly, and umbilical and inguinal hernias. Surviving children and patients with the infantile onset form (before 12 months of age) are characterized by a mucopolysaccharidosis-like phenotype that includes coarse facies, dysosotosis multiplex, kyphosis, short stature (with a slowing of growth towards 18 months of age), hepatosplenomegaly, hearing impairment, cherry-red spot on the retina (a constant feature after 3 years of age), corneal opacities (rarely) and speech and developmental delay, followed by psychomotor regression and myoclonus and ataxia in some cases. Renal disease (nephrosialidosis) has been reported in some patients. The juvenile form usually presents after the age of 2 with less pronounced coarse facies, angiokeratoma, myoclonic seizures, macular cherry red spots, and psychomotor regression.
ST-2 is due to a mutation of the N-acetyl-alpha-neuraminidase-1 (NEU1) gene (6p21) encoding the lysosomal enzyme neuraminidase, that initiates the degradation of sialoglycoconjugates in lysosomes. Mutations lead to a deficiency in enzyme activity and consequently to an accumulation of sialyloligosaccharides in tissues. In general, a higher residual neuraminidase activity is associated with milder symptoms and a longer lifespan.
An ophthalmological examination (fundoscopy) can visualize the bilateral macular cherry-red spots. Neuroimaging shows varying degrees of brain and cerebellar atrophy. The diagnosis is suspected by detection of urinary sialyloligosaccharide excretion and must be confirmed by demonstration of the neuraminidase enzyme deficiency (in the presence of normal beta-galactosidase activity) in leukocytes or, preferably, in cultured fibroblasts. Molecular genetic testing revealing causal mutation(s) can also confirm the diagnosis. The presence of echographic signs (such as hydrops, edema, ascites) may aid in diagnosing antenatal forms during pregnancy.
The main differential diagnoses include galactosialidosis (characterized by deficiencies in both beta galactosidase and neuraminidase) and mucopolysaccharidosis type 1, 2 or 6 (see these terms). Many patients of the juvenile sub-group, in particular, may appear to have a form of galactosialidosis.
Prenatal diagnosis can be performed by measurement of enzyme activity or by molecular genetic analysis if the underlying molecular defect in the family is well established
ST-2 is inherited in an autosomal recessive manner. Genetic counseling is possible.
Management and treatment
There is no cure for ST-2 and management is multidisciplinary involving mainly palliative care. Anti-convulsants may be used to treat myoclonic seizures, but are only rarely effective. Hematopoietic stem cell transplantation has not been successful in preventing psychomotor regression, bone changes or nephrosialidosis.
The prognosis depends on the form of ST-2. The congenital form leads to still-birth or death within the first two years of life. For the other forms, life expectancy does not generally exceed two decades.