eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Sialidosis (Mucolipidosis I)

Author: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Coauthor(s): William B Rizzo, MD, Professor, Department of Pediatrics, University of Nebraska Medical Center; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine
Contributor Information and Disclosures

Updated: Aug 4, 2008

Introduction

Background

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.

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.

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.

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.¹  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

• 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.
• Type II congenital form: These infants are delivered either stillborn or they die within the first 2 years of life.
• Type I adult form: These 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

• Infantile form: Onset of symptoms occurs in infants aged 0-12 months.
• Congenital form: Development of symptoms occurs in utero, and symptoms are present at birth.
• Adult form: The cherry-red spot may develop in the second decade of life, with myoclonus and ataxia developing later.

Clinical

History

• In general, sialidosis is a heterogenous disorder with a wide spectrum of variability in disease manifestation.
• Patients with the type II infantile form may be normal or almost normal in appearance at birth. Coarse facial features, developmental delay, and hepatosplenomegaly may develop within the first year of life.
  • Although not as severe as the Hurler phenotype, similar-appearing coarse features, hepatosplenomegaly, and skeletal abnormalities (dysostosis multiplex) become more pronounced with time. Short stature may also progressively develop.
  • The extent of neurologic progression varies, but macrocephaly, hypotonia, nystagmus, visual impairment, and myoclonic seizures are known to develop. Cherry-red spots appear with age in most patients. As the neurologic picture progresses, these patients become nonambulatory and are unable to care for themselves.
  • In the congenital form, hepatosplenomegaly, ascites, and hydrops fetalis are noted at birth, and the infant may be stillborn. In those who survive postnatally, the course is rapidly progressive.
• Patients with the adult form of the disease first report visual impairment due to color blindness or night blindness. Cherry-red spots are present in virtually all such patients. Myoclonus, which can be disabling, and ataxia develop later.

Physical

• Neurologic findings
  • Developmental delay or mental retardation
  • Visual impairment or loss of visual acuity
  • Hypotonia
  • Myoclonus
  • Nystagmus, ataxia, and seizures (have been reported)
• Coarse facial features
  • High forehead, puffy eyelids, epicanthal folds
  • Flat nasal bridge, anteverted nares, long philtrum
  • Gingival hypertrophy, macroglossia
• Skeletal abnormalities
  • Lumbar gibbus deformity and kyphoscoliosis
  • Joint stiffness and contractures (may develop)
• Ophthalmologic findings - Cherry-red macula, corneal opacities, lens opacities, or lamellar cataracts
• Abdomen - Hepatosplenomegaly in patients with the type II form as a result of visceral storage
• Congenital form
  • Hydrops fetalis, neonatal ascites
  • Hepatosplenomegaly, inguinal hernia

Causes

Sialidosis is an autosomal recessive disorder caused by an isolated deficiency of the enzyme, alpha-N -acetyl neuraminidase (also called sialidase). Three distinct human neuraminidases are known and are specifically localized to the cytosol, plasma membrane, and lysosome. The lysosomal enzyme is selectively deficient in human sialidosis. The lysosomal neuraminidase gene maps to chromosome 6p21 and has been cloned. Various enzyme-inactivating mutations have been identified in patients with sialidosis.

The variability of disease manifestation due to this enzyme deficiency, as evidenced by the 3 disease subtypes, has indicated a potential genotype-phenotype correlation. Research has shown that the type of gene mutation affects not only enzyme activity but also whether the enzyme localizes to the lysosome. Preliminary studies indicate that both of these properties have positively correlated with the clinical subtype of sialidosis.² However, the wide variability of clinical presentation in these patients cannot be fully explained by alpha-N -acetyl neuraminidase mutations. Therefore, other environmental or genetic factors probably account for the varying degrees of disease severity.

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