Background
Sialidosis, also known as mucolipidosis type I (ML I), is a rare inherited lysosomal storage disease that has clinical and histologic findings similar to the mucopolysaccharidoses and the sphingolipidoses. In the late 1960s, a small number of patients with mild Hurlerlike facies, skeletal dysplasia, psychomotor retardation, and normal excretion of urinary mucopolysaccharides were reported. Initially classified as a lipomucopolysaccharidosis, this disease was later classified into the group of similar diseases now known as the mucolipidoses. Patients with ML I were subsequently found to have an isolated deficiency of alpha-N -acetyl neuraminidase (sialidase) in leukocytes and cultured fibroblasts and, thus, have increased amounts of sialyloligosaccharide in the urine. At least 40 disease-causing mutations in the neuraminidase 1 (NEU1) gene have been reported.
Because of the neuraminidase deficiency, ML I is now categorized with the sialidoses, a group of biochemically distinct disease entities due to an isolated neuraminidase deficiency. Although the names are synonymous, this chapter refers to ML I by the newer name, sialidosis.
Two major clinical phenotypes of sialidosis are recognized; they are distinguished by the presence or absence of dysmorphic features and other somatic changes. Patients with type I disease have been referred to as having "cherry-red spot-myoclonus" syndrome. These patients typically develop symptoms of myoclonic epilepsy, visual problems, and ataxia in the second or third decade of life. Macular cherry red spots are always present. The myoclonus is aggravated by smoking and menses, among other factors, and may become debilitating.
Myoclonic seizures are poorly controlled by the standard antiepileptics. Patients with the type II form of sialidosis have an earlier onset of symptoms and exhibit dysmorphic and somatic features that progressively worsen. Type II can be further divided into an infantile onset form and a more severe congenital onset form. The infantile form presents in the first year of life with the appearance of coarse, Hurlerlike facies; hepatomegaly; bony changes of dysostosis multiplex; and early developmental delay. The reported incidence of cherry-red spots is less than 75%, in contrast to the virtual 100% in patients with the type I form. The more severe congenital form of type II sialidosis has onset in utero and results in hydrops fetalis, hepatomegaly, and either still birth or death within a period of months.
Some patients have been described with a clinical phenotype consistent with type II sialidosis and a combined deficiency of neuraminidase and beta-galactosidase. However, the biochemical basis for the combined enzyme deficiency is a loss of a protective protein that interacts with both enzymes to produce catalytic activity. Hence, this is a genetically and biochemically distinct entity from sialidosis. Sialidosis should not be confused with disorders of free sialic acid storage, which are caused by a defect in the lysosomal transport of free sialic acid due to mutations in the AST (anion and sugar transporter) gene.
Pathophysiology
In lysosomal storage disorders, the deficiency of a specific lysosomal enzyme interrupts the normal catabolic pathway, resulting in the cellular accumulation of substrates ordinarily degraded by that enzyme. The specificity of these accumulated materials to the distinct enzyme defect is striking in the lysosomal disorders, and the accumulation then leads to abnormal cell architecture. Precisely how the changes in cellular structure due to storage translates into adverse effects on cell function remains enigmatic. Some evidence implicates neuraminidase in regulation of intracellular trafficking of the lysosomal LAMP-1 membrane protein; LAMP-1 may be instrumental in lysosomal exocytosis. Further research is needed to fully explain the role of neuraminidase in this process. [1, 2]
The clinical course of the disease depends on the associated effects of progressive storage in the organ systems where these substrates are highly concentrated. In sialidosis, the deficiency of lysosomal alpha-N -acetyl neuraminidase prevents the normal degradation of glycoproteins containing sialic acid residues. This results in intracellular storage of excess sialyloligosaccharides and is histologically observed as abnormal vacuolization of various cell types. Whereas bone marrow and circulating lymphocytes are highly vacuolated in type II sialidosis, these findings are conspicuously absent in type I disease. The organ systems mostly involved in sialidosis include the CNS, the skeletal system, and the reticuloendothelial system.
Epidemiology
Frequency
International
Sialidosis is a rare disorder that has no racial predilection. Very little population data are available, but a study from the Netherlands reported a frequency of approximately 1 case in 2,175,000 live births. [3] However, this rate may not apply to all populations, some of which could have a higher incidence; moreover, missed clinical recognition is an important factor when newborn screening is not an option.
Mortality/Morbidity
In the type II infantile form, death usually occurs by the second decade of life, but survival into the early third decade of life has been reported. In the type II congenital form, infants are delivered either stillborn or they die within the first 2 years of life. In type I adult form, patients usually do not die from the disease but they experience decreased visual acuity, and myoclonus often interferes with walking.
Race
Sialidosis is panracial.
Sex
Sialidosis is inherited as an autosomal recessive trait. Both sexes are affected with equal frequency.
Age
In the infantile form, onset of symptoms occurs in infants aged 0-12 months. In the congenital form, development of symptoms occurs in utero, and symptoms are present at birth. In the adult form, the cherry-red spot may develop in the second decade of life, with myoclonus and ataxia developing later.
Prognosis
In patients with type II infantile onset, psychomotor retardation and neurologic deterioration is progressive, and death from cardiorespiratory complications usually occurs by the second decade of life.
Patient Education
Care must be taken to educate families about the genetic basis of this disorder, including recurrence risks, identification of carriers, and the availability of prenatal diagnosis for future at-risk pregnancies.
